1. Field of the Invention
The present invention relates to novel compounds, compounds and pharmaceutical compositions thereof, and to methods of using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy eating feeding disorders, irritable bowel syndrome, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, and fertility problems.
2. Description of the Related Art
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland (J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)). In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain (W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)). There is also evidence demonstrating that CRF may also play a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors (J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)).
Clinical data have demonstrated that CRF may have implications in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and eating disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system (for review see E. B. De Souza, Hosp. Practice 23:59 (1988)).
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals (C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al. Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol. Psychiatry 25:355 (1989)). Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF (C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)). In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients (P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)). Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression (R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)). There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the number of CRF receptors in brain (Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)).
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models (D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)). Preliminary studies using the putative CRF receptor antagonist xcex1-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines (C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)). Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test (K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)) and in the acoustic startle test (N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)) in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF (K. T. Britton et al., Psychopharmacology 94:306 (1988)).
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized, however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines (for review, see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p.221 (1990)).
In order to study these specific cell-surface receptor proteins, compounds must be identified that can interact with the CRF receptor in a specific manner dictated by the pharmacological profile of the characterized receptor. Toward that end, there is evidence that the direct CRF antagonist compounds and compositions of this invention, which can attenuate the physiological responses to stress-related disorders, will have potential therapeutic utility for the treatment of depression and anxiety-related disorders. All of the aforementioned references are hereby incorporated by reference.
U.S. Pat. Nos. 4,788,195 and 4,876,252 teach the synthesis of compounds with the general formula (A): 
The utility of these compounds is described as treatment of asthma, allergic diseases, inflammation, and diabetes in mammals.
PCT application WO 89/01938 describes the synthesis and utility of compounds with the formula (B): 
These compounds can be utilized in the treatment of neurologic diseases, having an effect of regenerating and repairing nerve cells and improving and restoring learning and memory.
U.S. Pat. No. 4,783,459 describes the utility and synthesis of compounds with the following general formula (C): 
The compounds have activity as fungicides, especially against fungal diseases of plants.
U.S. Pat. No. 4,992,438 discloses the utility and synthesis of compounds with the following general formula: 
The utility of these compounds is described as fungicides with a broad spectrum activity against plant pathogenic fungi.
European Patent Application 0 013 143 A2 discloses the utility and synthesis of compounds with the following general formula: 
These compounds are described as pre- and post-emergence herbicides.
U.S. Pat. No. 5,063,245 discloses a method of producing CRF antagonism with compounds with the general formulae: 
PCT application WO 91/18887 discloses compounds of the general formula: 
wherein R2 may be C1-C4 alkyl and R3 may be substituted phenyl, said compounds being useful for the inhibition of gastric acid secretion.
European patent application EP 0588762 A1 discloses compounds of the general formula: 
wherein R4 may be C1-C3 alkyl, said compounds being useful as protein kinase C inhibitors and antitumor agents. The application also generally discloses the use of these compounds for the treatment of AIDS, atherosclerosis, and cardiovascular and central nervous system disorders.
European patent application EP 336494 A2 discloses compounds of the general formula: 
wherein X may be Nxe2x80x94R4 and R4 may be (un)substituted alkyl, said compounds being useful as herbicides.
U.S. Pat. No. 3,988,338 discloses compounds of the general formula: 
wherein Rxe2x80x3xe2x80x3 may be an optionally substituted phenyl, said compounds having anticytokinin activity.
European patent application EP 0563001 A1 discloses compounds of the general formula: 
said compounds having claimed utility for the treatment of psychosis, depression, and convulsive disorders.
European patent application EP 0155911 A1 discloses compounds of the general formula: 
wherein R3 may be substituted phenyl, said compounds being useful as herbicides.
Australian patent AU 8425873 A discloses compounds of the general formula: 
wherein R2 may be a substituted phenyl group, said compounds being useful as antiulcer agents.
Eswaran et al, Org. Prep. Proced. Int. 24(1):71-3, (1992), discloses the use of related 5,7-diazaindoles as synthetic intermediates. El-Bayouki et al, J. Heterocycl. Chem. 22(3):853-6, (1985) discloses the use of related 5,7-diazaisoindazoles as synthetic intermediates.
The compounds and methods of the present invention provide the methodology for the production of specific high-affinity compounds capable of inhibiting the action of CRF at its receptor protein in the brain. These compounds should be useful in the treatment of a variety of neurodegenerative, neuropsychiatric and stress-related disorders such as irritable bowel syndrome, immune suppression. Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, and fertility problems. It is further asserted that this invention may provide compounds and pharmaceutical compositions suitable for use in such a method. Further advantages of this invention will be clear to one skilled in the art from the reading of the description that follows.
The present invention relates to compositions and methods of use and preparation of N-alkyl-N-aryl-pyrimidinamines and derivatives thereof. These compounds interact with and have antagonist activity at the CRF receptor and would thus have some therapeutic effect on psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress and eating disorders, supranuclear palsy, irritable bowel syndrome, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, and fertility problems.
Novel compounds of this invention include compounds of formula: 
or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is CR3a, N, or CR29;
when Y is CR3a or N:
R1 is independently selected at each occurrence from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen, C1-C2 haloalkyl, NR6R7, OR8, and S(O)nR8;
R3 is C1-C4 alkyl, aryl, C3-C6 cycloalkyl, C1-C2 haloalkyl, halogen, nitro, NR6R7, OR8, S(O)nR8, C(xe2x95x90O)R9, C(xe2x95x90O)NR6R7, C(xe2x95x90S)NR6R7, xe2x80x94(CHR16)kNR6R7, (CH2)kOR8, C(xe2x95x90O)NR10CH(R11)CO2R12, xe2x80x94C(OH)(R25)(R25a), xe2x80x94(CH2)pS(O)n-alkyl, xe2x80x94(CHR16)R25, xe2x80x94C(CN)(R25)(R16) provided that R25 is not xe2x80x94NH-containing rings, xe2x80x94C(xe2x95x90O)R25, xe2x80x94CH(CO2R16)2, NR10C(xe2x95x90O)CH(R11)NR10R12, NR10CH(R11)CO2R12; substituted C1-C4 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, substituted C1-C4 alkoxy, aryl-(substituted C1-C4) alkyl, aryl-(substituted C1-C4) alkoxy, substituted C3-C6 cycloalkyl, amino-(substituted C1-C4) alkyl, substituted C1-C4 alkylamino, where substitution by R27 can occur on any carbon containing substituent; 2-pyridinyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl, phenyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, imidazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl; or 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
J, K, and L are independently selected at each occurrence from the group of N, CH, and CXxe2x80x2;
M is CR5 or N;
V is CR1a or N;
Z is CR2 or N;
R1a, R2, and R3a are independently selected at each occurrence from the group consisting of hydrogen, halo, halomethyl, C1-C3 alkyl, and cyano;
R4 is (CH2)mOR16, C1-C4 alkyl, allyl, propargyl, (CH2)mR13, or xe2x80x94(CH2)mOC(O)R16;
X is halogen, S(O)2R8, SR8, halomethyl, xe2x80x94(CH2)pOR8, xe2x80x94OR8, cyano, xe2x80x94(CHR16)pNR14R15, xe2x80x94C(xe2x95x90O)R8, C1-C6 alkyl, C4-C10 cycloalkylalkyl, C1-C10alkenyl, C2-C10alkynyl, C1-C10alkoxy, aryl-(C2-C10)-alkyl, C3-C6 cycloalkyl, aryl-(C1-C10)-alkoxy, nitro, thio-(C1-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, xe2x80x94C(xe2x95x90NOR16)H, or xe2x80x94C(xe2x95x90O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;
Xxe2x80x2 is independently selected at each occurrence from the group consisting of hydrogen, halogen, S(O)nR8, halomethyl, xe2x80x94(CHR16)pOR8, cyano, xe2x80x94(CHR16)pNR14R15, C(xe2x95x90O)R8, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, aryl-(C1-C10)-alkyl, C3-C6 cycloalkyl, aryl-(C1-C10)-alkoxy, nitro, thio-(C1-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, xe2x80x94C(xe2x95x90NOR16)H, and xe2x80x94C(xe2x95x90O)NR14R15, where substitution by R18 can occur on any carbon containing substituents;
R5 is halo, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, C1-C6 alkyl, C1-C3 haloalkyl, xe2x80x94(CHR16)pOR8, xe2x80x94(CHR16)pS(O)nR8, xe2x80x94(CHR16)pNR14R15, C314 C6 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl-(C2-C10)-alkyl, aryl-(C1-C10)-alkoxy, cyano, C3-C6 cycloalkoxy, nitro, amino-(C1-C10)-alkyl, thio-(C2-C10)-alkyl, SOn(R8), C(xe2x95x90O)R8, xe2x80x94C(xe2x95x90NOR16)H, or xe2x80x94C(xe2x95x90O)NR14R15, where substitution by R18 can occur on any carbon containing substituents;
R6 and R7 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, (C4-C12)-cycloalkylalkyl, xe2x80x94(CH2)kR13, (CHR16)pOR8, xe2x80x94(C1-C6alkyl)-aryl, heteroaryl, aryl, xe2x80x94S(O)2-aryl or xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl wherein the aryl or heteroaryl groups are optionally substituted with 1-3 groups selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, nitro, carboxy, CO2(C1-C6 alkyl), cyano, and S(O)zxe2x80x94(C1-C6-alkyl); or can be taken together to form xe2x80x94(CH2)qA(CH2)rxe2x80x94, optionally substituted with 0-3 R17; or, when considered with the commonly attached nitrogen, can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-3 groups consisting of hydrogen, C1-C6 alkyl, hydroxy, or C1-C6 alkoxy;
A is CH2, O, NR25, C(xe2x95x90O), S(O)n, N(C(xe2x95x90O)R17), N(R19), C(H)(NR14R15), C(H)(OR20), C(H)(C(xe2x95x90O)R21), or N(S(O)nR21);
R8 is independently selected at each occurrence from the group consisting of hydrogen; C1-C6 alkyl; xe2x80x94(C4-C12) cycloalkylalkyl; (CH2)tR22; C3-C10 cycloalkyl; xe2x80x94NR6R7; aryl; xe2x80x94NR16(CH2)nNR6R7; xe2x80x94(CH2)kR25; and (CH2)theteroaryl or (CH2)taryl, either of which can optionally be substituted with 1-3 groups selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, nitro, carboxy, CO2(C1-C6 alkyl), cyano, and S(O)z(C1-C6-alkyl);
R9 is independently selected at each occurrence from R10, hydroxy, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, aryl substituted with 0-3 R18, and xe2x80x94(C1-C6 alkyl)-aryl substituted with 0-3 R18;
R10, R16, R23, and R24 are independently selected at each occurrence from hydrogen or C1-C4 alkyl;
R11 is C1-C4 alkyl substituted with 0-3 groups chosen from the following: keto, amino, sulfhydryl, hydroxyl, guanidinyl, p-hydroxyphenyl, imidazolyl, phenyl, indolyl, indolinyl,
or, when taken together with an adjacent R10, are (CH2)t;
R12 is hydrogen or an appropriate amine protecting group for nitrogen or an appropriate carboxylic acid protecting group for carboxyl;
R13 is independently selected at each occurrence from the group consisting of CN, OR19, SR19, and C3-C6 cycloalkyl;
R14 and R15 are independently selected at each occurrence from the group consisting of hydrogen, C4-C10 cycloalkyl-alkyl, and R19;
R17 is independently selected at each occurrence from the group consisting of R10, C1-C4 alkoxy, halo, OR23, SR23, NR23R24, and (C1-C6) alkyl (C1-C4) alkoxy;
R18 is independently selected at each occurrence from the group consisting of R10, hydroxy, halogen, C1-C2 haloalkyl, C1-C4 alkoxy, C(xe2x95x90O)R24, and cyano;
R19 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)wR22, and aryl substituted with 0-3 R18;
R20 is independently selected at each occurrence from the group consisting of R10, C(xe2x95x90O)R31, and C2-C4 alkenyl;
R21 is independently selected at each occurrence from the group consisting of R10, C1-C4 alkoxy, NR23R24, and hydroxyl;
R22 is independently selected at each occurrence from the group consisting of cyano, OR24, SR24, NR23R24, C1-C6 alkyl, C3-C6 cycloalkyl, xe2x80x94S(O)nR31, and xe2x80x94C(xe2x95x90O)R25;
R25, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrazolyl, thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
R25a, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of H and R25;
R27 is independently selected at each occurrence from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 alkoxy, aryl, nitro, cyano, halogen, aryloxy, and heterocycle optionally linked through O;
R31 is independently selected at each occurrence from the group consisting of C1-C4 alkyl, C3-C7 cycloalkyl, C4-C10 cycloalkyl-alkyl, and aryl-(C1-C4) alkyl;
k, m, and r are independently selected at each occurrence from 1-4;
n is independently selected at each occurrence from 0-2;
p, q, and z are independently selected at each occurrence from 0-3;
t and w are independently selected at each occurrence from 1-6,
provided that when J is CXxe2x80x2 and K and L are both CH, and M is CR5, then
(A) when V and Y are N and Z is CH and R1 and R3 are methyl,
(1) and R4 is methyl, then
(a) R5 can not be methyl when X is OH and Xxe2x80x2 is H;
(b) R5 can not be xe2x80x94NHCH3 or xe2x80x94N(CH3)2 when X and Xxe2x80x2 are xe2x80x94OCH3; and
(c) R5 can not be xe2x80x94N(CH3)2 when X and Xxe2x80x2 are xe2x80x94OCH2CH3;
(2) and R4 is ethyl, then
(a) then R5 can not be methylamine when X and Xxe2x80x2are xe2x80x94OCH3;
(b) R5 can not be OH when X is Br and Xxe2x80x2 is OH; and
(c) R5 can not be xe2x80x94CH2OH or xe2x80x94CH2N(CH3)2 when X is xe2x80x94SCH3 and Xxe2x80x2 is H;
(B) when V and Y are N, Z is CH, R4 is ethyl, R5 is iso-propyl, X is Br, Xxe2x80x2 is H, and
(1) R1 is CH3, then
(a) R3 can not be OH, piperazin-1-yl, xe2x80x94CH2-piperidin-1-yl, xe2x80x94CH2xe2x80x94(N-4-methylpiperazin-1-yl), xe2x80x94C(O)NH-phenyl, xe2x80x94CO2H, xe2x80x94CH2O-(4-pyridyl), xe2x80x94C(O)NH2, 2-indolyl, xe2x80x94CH2O-(4-carboxyphenyl), xe2x80x94N(CH2CH3)(2-bromo-4-isopropylphenyl);
(2) R1 is xe2x80x94CH2CH2CH3 then R3 can not be xe2x80x94CH2CH2CH3;
(C) when V, Y and Z are N, R4 is ethyl, and
(1) R5 is iso-propyl, X is bromo, and Xxe2x80x2 is H, then
(a) R3 can not be OH or xe2x80x94OCH2CN when R1 is CH3; and
(b) R3 can not be xe2x80x94N(CH3)2 when R1 is xe2x80x94N(CH3)2;
(2) R5 is xe2x80x94OCHxe2x80x94, X is xe2x80x94OCH3, and Xxe2x80x2 is H, then R3 and R1 can not both be chloro;
further provided that when J, K, and L are all CH and M is CR5, then
(D) at least one of V, Y, and Z must be N;
(E) when V is CR1a, Z and Y can not both be N;
(F) when Y is CR3a, Z and V can not both be N;
(G) when Z is CR2, V and Y must both be N;
(H) Z can be N only when both V and Y are N or when V is CR1a and Y is CR3a;
(I) when V and Y are N, Z is CR2, and R2 is H or C1-C3 alkyl, and R4 is C1-C3 alkyl, R3 can not be 2-pyridinyl, indolyl, indolinyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-phenothiazinyl, or 4-pyrazinyl;
(J) when V and Y are N; Z is CR2; R2 is H or C1-C3 alkyl; R4 is C1-C4 alkyl; R5, X, and/or Xxe2x80x2 are OH, halo, CF3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, cyano, amino, carbamoyl, or C1-C4 alkanoyl; and R1 is C1-C4 alkyl, then R3 can not be xe2x80x94NH(substituted phenyl) or xe2x80x94N(C1-C4 alkyl)(substituted phenyl);
and wherein, when Y is CR29:
J, K, L, M, Z, A, k, m, n, p, q, r, t, w, R3, R10, R11, R12, R13, R16, R18, R19, R21, R23, R24, R25, and R27 are as defined above and R25a, in addition to being as defined above, can also be C1-C4 alkyl, but
V is N;
R1 is C1-C2 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 alkoxy, halogen, amino, methylamino, dimethylamino, aminomethyl, or N-methylaminomethyl;
R2 is independently selected at each occurrence from the group consisting of hydrogen, halo, C1-C3 alkyl, nitro, amino, and xe2x80x94CO2R10;
R4 is taken together with R29 to form a 5-membered ring and is xe2x80x94C(R28)xe2x95x90 or xe2x80x94Nxe2x95x90 when R29 is xe2x80x94C(R30)xe2x95x90 or xe2x80x94Nxe2x95x90, or xe2x80x94CH(R28)xe2x80x94 when R29 is xe2x80x94CH(R30)xe2x80x94;
X is Cl, Br, I, S(O)nR8, OR8, halomethyl, xe2x80x94(CHR16)pOR8, cyano, xe2x80x94(CHR16)pNR14R15, C(xe2x95x90O)R8, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, aryl-(C1-C10)-alkyl, C3-C6 cycloalkyl, aryl-(C1-C10 )-alkoxy, nitro, thio-(C1-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, xe2x80x94C(xe2x95x90NOR16)H, or C(xe2x95x90O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;
Xxe2x80x2 is hydrogen, Cl, Br, I, S(O)nR8, xe2x80x94(CHR16)pOR8, halomethyl, cyano, xe2x80x94(CHR16)pNR14R15, C(xe2x95x90O)R8, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10, alkoxy, aryl-(C1-C10)-alkyl, C3-C6 cycloalkyl, aryl-(C2-C10)-alkoxy, nitro, thio-(C2-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, xe2x80x94C(xe2x95x90NOR16)H, or C(xe2x95x90O)NR8R15 where substitution by R18 can occur on any carbon containing substituents;
R5 is halo, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, C1-C6 alkyl, C1-C3 haloalkyl, C1-C6 alkoxy, (CHR16)pOR8, (CHR16)pS(O)nR8, (CHR16)pNR14R15, C3-C6 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl-(C2-C10)-alkyl, aryl-(C1-C10)-alkoxy, cyano, C3-C6 cycloalkoxy, nitro, amino-(C1-C10)-alkyl, thio-(C1-C10)-alkyl, SOn(R8), C(xe2x95x90O)R8, xe2x80x94C(xe2x95x90NOR16)H, or C(xe2x95x90O)NR8R15 where substitution by R18 can occur on any carbon containing substituents;
R6 and R7 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)kR13, (C4-C12)-cycloalkylalkyl, C1-C6 alkoxy, xe2x80x94(C1-C6 alkyl)-aryl, heteroaryl, aryl, xe2x80x94S(O)z-aryl or xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl wherein the aryl or heteroaryl groups are optionally substituted with 1-3 groups selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, nitro, carboxy, CO2(C1-C6 alkyl), and cyano; or can be taken together to form xe2x80x94(CH2)qA(CH2)rxe2x80x94, optionally substituted with 0-3 R17; or, when considered with the commonly attached nitrogen, can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-3 groups consisting of hydrogen, C1-C6 alkyl, hydroxy, or C1-C6 alkoxy;
R8 is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, xe2x80x94(C4-C12) cycloalkylalkyl, (CH2)tR22, C3-C10 cycloalkyl, xe2x80x94(C1-C6 alkyl)-aryl, heteroaryl, xe2x80x94NR16, xe2x80x94N(CH2)nNR6R7; xe2x80x94(CH2)kR25, xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, nitro, carboxy, CO2(C1-C6 alkyl), and cyano;
R9 is independently selected at each occurrence from R10, hydroxy, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, and aryl substituted with 0-3 R18;
R14 and R15 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)tR22, and aryl substituted with 0-3 R18;
R17 is independently selected at each occurrence from the group consisting of R10, C1-C4 alkoxy, halo, OR23, SR23, and NR23R24;
R20 is independently selected at each occurrence from the group consisting of R10 and C(xe2x95x90O)R31;
R22 is independently selected at each occurrence from the group consisting of cyano, OR24, SR24, NR23R24, C3-C6 cycloalkyl, xe2x80x94S(O)nR31, and xe2x80x94C(xe2x95x90O)R25;
R26 is hydrogen or halogen:
R28 is C1-C2 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, hydrogen, C1-C2 alkoxy, halogen, or C2-C4 alkylamino;
R29 is taken together with R4 to form a five membered ring and is: xe2x80x94CH(R30)xe2x80x94 when R4 is xe2x80x94CH(R28)xe2x80x94, xe2x80x94C(R30)xe2x95x90 or xe2x80x94Nxe2x95x90 when R4 is xe2x80x94C(R28)xe2x95x90 or xe2x80x94Nxe2x95x90;
R30 is hydrogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, halogen, C1-C2 alkenyl, nitro, amido, carboxy, or amino;
R31 is C1-C4 alkyl, C3-C7 cycloalkyl, or aryl-(C1-C4) alkyl;
provided that when J, K, and L are all CH, M is CR5, Z is CH, R3 is CH3, R28 is H, R5 is iso-propyl, X is Br, Xxe2x80x2 is H, and R1 is CH3, then R30 can not be H, xe2x80x94CO2H, or xe2x80x94CH2NH2;
and further provided that when J, K and L are all CH; M is CR5; Z is N; and
(A) R29 is xe2x80x94C(R1)xe2x95x90; then one of R28 or R30 is hydrogen;
(B) R29 is N; then R3 is not halo, NH2, NO2, CF3, CO2H, CO2-alkyl, alkyl, acyl, alkoxy, OH, or xe2x80x94(CH2)mOalkyl;
(C) R29 is N; then R28 is not methyl if X or Xxe2x80x2 are bromo or methyl and R5 is nitro; or
(D) R29 is N, and R1 is CH3 and R3 is amino; then R5 is not halogen or methyl.
Preferred compounds of this invention are those compounds of Formula I wherein,
Y is CR3a or N:
R3 is C1-C4 alkyl, aryl, halogen, C1-C2 haloalkyl, nitro, NR6R7, OR8, SR8, C(xe2x95x90O)R9, C(xe2x95x90O)NR6R7, C(xe2x95x90S)NR6R7, (CH2)kNR6R7, (CH2)kOR8, C(xe2x95x90O)NR10CH(R11)CO2R12, xe2x80x94(CHR16)pOR8, xe2x80x94C(OH)(R25)(R25a), xe2x80x94(CH2)pS(O)n-alkyl, xe2x80x94C(CN)(R25)(R16) provided that R25 is not an xe2x80x94NHxe2x80x94 containing ring, xe2x80x94C(xe2x95x90O)R25, xe2x80x94CH(CO2R16)2, NR10C(xe2x95x90O)CH(R11)NR10R12; substituted C1-C4alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, C3-C6 cycloalkyl, substituted C1-C4 alkoxy, aryl-(substituted C1-C4) alkyl, aryl-(substituted C1-C4) alkoxy, substituted C3-C6 cycloalkyl, amino-(substituted C1-C4)alkyl, substituted C1-C4 alkylamino, where substitution by R27 can occur on any carbon containing substituent; 2-pyridinyl, indolinyl, indolyl, pyrazoyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, or 5-methyl-2-thienyl, azetidinyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, azocinyl, azepinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, imidazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiazolyl, triazinyl; or 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
J, K, and L are independently selected at each occurrence from the group consisting of CH and CXxe2x80x2;
M is CR5;
R1a, R2, and R3a are independently selected at each occurrence from the group consisting of hydrogen, halo, methyl, or cyano;
X is halogen, S(O)2R8, SR8 halomethyl, (CH2)pOR8, cyano, xe2x80x94(CHR16)pNR14R15, C(xe2x95x90O)R8, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, aryl-(C1-C10)-alkyl, C3-C6 cycloalkyl, aryl-(C1-C10)-alkoxy, nitro, thio-(C1-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, -C(xe2x95x90NOR16)H, or xe2x80x94C(xe2x95x90O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;
Xxe2x80x2 is hydrogen, halogen, S(O)nR8, halomethyl, (CH2)pOR8, cyano, xe2x80x94(CHR16)pNR14R15, C(xe2x95x90O)R8, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, aryl-(C1-C10-alkyl, C3-C6 cycloalkyl, aryl-(C1-C10)-alkoxy, nitro, thio-(C1-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16) xe2x80x94C1-C4-alkyl, xe2x80x94C(xe2x95x90NOR16)H, or xe2x80x94C(xe2x95x90O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;
R5 is halo, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, C1-C6 alkyl, C1-C3 haloalkyl, C1-C6 alkoxy, (CHR16)pOR8, (CHR16)pS(O)nR8, (CHR16)pNR14R15, C3-C6 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl-(C2-C10)-akyl, aryl-(C2-C10)-alkoxy, cyano, C3-C6 cycloalkoxy, nitro, amino-(C2-C10)-alkyl, thio-(C2-C10)-alkyl, SOn(R8), C(xe2x95x90O)R8, xe2x80x94C(xe2x95x90NOR16)H, or C(xe2x95x90O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;
R6 and R7 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, cycloalkylalkyl, xe2x80x94(CH2)kR13, C1-C6 alkoxy, xe2x80x94(CHR16)pOR8, xe2x80x94(C1-C6 alkyl)-aryl, aryl, heteroaryl, xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl, wherein the aryl or heteroaryl groups are optionally substituted with 1-3 groups selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, carboxy, CO2(C1-C6 alkyl), cyano, or can be taken together to form xe2x80x94(CH2)qA(CH2)rxe2x80x94, optionally substituted with 0-3 R17, or, when considered with the commonly attached nitrogen, can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-3 groups consisting of hydrogen, C1-C6 alkyl, (C1-C6)alkyl(C1-C4)alkoxy, and C1-C6 alkoxy;
R8 is independently selected at each occurrence from the group consisting of hydrogen; C1-C6 alkyl; xe2x80x94(C4-C12) cycloalkylalkyl; (CH2)tR22; C3-C10 cycloalkyl; xe2x80x94NR6R7; aryl; xe2x80x94NR16(CH2)nNR6R7; xe2x80x94(CH2)kR25; and CH2)theteroaryl or (CH2)taryl, either of which can optionally be substituted with 1-3 groups selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, carboxy, and CO2(C1-C6 alkyl);
R10 is hydrogen;
R13 is independently selected at each occurrence from the group consisting of OR19, SR19, and C3-C6 cycloalkyl;
R14 and R15 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C4-C10 cycloalkyl-alkyl;
R17 is independently selected at each occurrence from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and (C1-C6)alkyl(C1-C4)alkoxy;
R19 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and aryl substituted with 0-3 R18;
R22 is independently selected at each occurrence from the group consisting of cyano, OR24 SR24, NR23R24, C3-C6 cycloalkyl, xe2x80x94S(O)nR31, and xe2x80x94C(xe2x95x90O)R25;
R25, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, azocinyl, benzofuranyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, triazinyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
R25a, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of H, phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, azocinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
t is independently selected at each occurrence from 1-3; and
w is 1-3.
Other preferred compounds of this invention are those compounds of Formula I wherein,
Y is CR29;
Z is CR2;
R1 is methyl, amino, chloro, or methylamino;
R2 is hydrogen;
R3 is C1-C4 alkyl, aryl, halogen, nitro, NR6R7, OR8, SR8, C(xe2x95x90O)R9, C(xe2x95x90O)NR6R7, (CH2)kNR6R7, (CH2)kOR8, xe2x80x94C(OH)(R25)(R25a), xe2x80x94(CH2)pS(O)n-alkyl, xe2x80x94C(xe2x95x90O)R25, xe2x80x94CH(CO2R16)2; substituted C1-C4alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, C3-C6 cycloalkyl, substituted C1-C4 alkoxy, aryl-(substituted C1-C4) alkyl, aryl-(substituted C1-C4) alkoxy, substituted C3-C6 cycloalkyl, amino-(substituted C1-C4) alkyl, substituted C1-C4 alkylamino, or is N-linked piperidinyl, piperazinyl, morpholino, thiomorpholino, imidazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, where substitution by R27 can occur on any carbon containing substituent;
J, K, and L are independently selected at each occurrence from the group consisting of CH and CXxe2x80x2;
M is CR5;
R4 is taken together with R29 to form a five membered ring and is xe2x80x94CHxe2x95x90;
X is Br, I, S(O)nR8, OR8, NR14R15, R18 substituted alkyl, or amino-(C1-C2) alkyl;
Xxe2x80x2 is hydrogen, Br, I, S(O)nR8, OR8, NR14R15, R18 substituted alkyl, or amino-(C1-C2) alkyl;
R5 is independently selected at each occurrence from the group consisting of halogen, -C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, C1-C6 alkyl, C1-C6 alkoxy, (CHR16)pOR8, xe2x80x94NR14R15, (CHR16)pS(O)nR8, (CHR16)pNR14R15, C3-C6 cycloalkyl, C(xe2x95x90O)R8, and C(xe2x95x90O)NR8R15; R6 and R7 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, xe2x80x94(CH2)kR13, (C3-C6)cycloalkyl-(C1-C6)alkyl, xe2x80x94(C1-C6 alkyl)-aryl, heteroaryl, xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl, wherein the aryl or heteroaryl groups are optionally substituted with 1-3 groups selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, amino, NHC(xe2x95x90O)(C1-C2 alkyl), NH(C1-C2alkyl), and N(C1-C2 alkyl)2, or can be taken together to form xe2x80x94(CH2)qA(CH2)rxe2x80x94, optionally substituted with 0-2 R17, or, when considered with the commonly attached nitrogen, can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-2 groups consisting of hydrogen, C1-C3 alkyl, hydroxy, or C1-C3 alkoxy;
A is CH2, O, NR25, C(xe2x95x90O), or S(O)n;
R8 is independently selected at each occurrence from the group consisting of hydrogen; C1-C6 alkyl; xe2x80x94(C4-C12) cycloalkylalkyl; (CH2)tR22; C3-C10 cycloalkyl; xe2x80x94NR6R7; aryl; xe2x80x94NR16(CH2)nNR6R7; xe2x80x94(CH2)kR25; and (CH2)theteroaryl or (CH2)taryl, either of which can optionally be substituted with 1-3 groups selected from the group consisting of hydrogen, C1-C2 alkyl, C1-C2 alkoxy, amino, NHC(xe2x95x90O)(C1-C2alkyl), NH(C1-C2alkyl), N(C1-C2 alkyl),, R9 is hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C3-C6 cycloalkyl substituted with 0-2 R18;
R14 and R15 are independently selected at each occurrence from the group consisting of hydrogen, C1-C2 alkyl, (CH2)tR22, and aryl substituted with 0-2 R18;
R16 is independently selected at each occurrence from the group consisting of hydrogen and C1-C2 alkyl;
R17 is independently selected at each occurrence from the group consisting of hydrogen, C1-C2 alkyl, C1-C2 alkoxy, halo, and NR23R24;
R18 is independently selected at each occurrence from the group consisting of hydrogen, C1-C2 alkyl, C1-C2alkoxy, halo, and NR23R24;
R22 is independently selected at each occurrence from the group consisting of OR24, SR24, R23R24, and xe2x80x94C(xe2x95x90O)R25;
R23 and R24 are independently selected at each occurrence from hydrogen and C1-C2 alkyl;
R25, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, azocinyl, benzofuranyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, triazinyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
R25a is independently selected at each occurrence from the group consisting of H and C1-C4 alkyl;
R29 is taken together with R4 to form a five membered ring and is xe2x80x94C(R30)xe2x95x90;
R30 is hydrogen, cyano, C1-C2 alkyl, or halogen;
k is 1-3;
p is 0-2;
q and r are 2; and
t and w are independently selected at each occurrence from 1-2.
More preferred compounds of this invention are those compounds of Formula I wherein, when Y is CR3a or N:
R1 is independently selected at each occurrence from the group consisting of C1-C2 alkyl, C1-C2 haloalkyl, NR6R7, and OR8;
R3 is independently selected at each occurrence from the group consisting of C1-C4 alkyl, C1-C2 haloalkyl, NR6R7, OR8, C(xe2x95x90O)R9, C(xe2x95x90O)NR6R7, (CH2)kNR6R7, (CH2)kOR8, xe2x80x94C(CN)(R25)(R16) provided that R25 is not an xe2x80x94NHxe2x80x94 containing ring, xe2x80x94C(OH)(R25)(R25a), xe2x80x94(CH2)pS(O)n-alkyl, xe2x80x94C(xe2x95x90O)R25, xe2x80x94CH(CO2R16)2, 2-pyridinyl, indolinyl, indolyl, pyrazoyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 1H-indazolyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4H-quinolizinyl, benzofuranyl, carbazolyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, imidazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiazolyl, triazinyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
R1a, R2, and R3a are independently selected at each occurrence from the group consisting of hydrogen, methyl, and cyano;
X is Cl, Br, I, OR8, NR14R15, (CH2)mOR16, or (CHR16)NR14R15;
Xxe2x80x2 is hydrogen, Cl, Br, I, OR8, NR14R15, (CH2)mOR16, or (CHR16)NR14R15;
R5 is halo, C1-C6 alkyl, C1-C3 haloalkyl, C1-C6 alkoxy, (CHR16)pOR8, (CHR16)pNR14R15, or C3-C6 cycloalkyl;
R6 and R7 are independently selected at each occurrence from the group consisting of
C1-C6 alkyl, (CHR16)pOR8, C1-C6 alkoxy, and xe2x80x94(CH2)kR13, or can be taken together to form xe2x80x94(CH2)qA(CH2)rxe2x80x94, optionally substituted with xe2x80x94CH2OCH3;
A is CH2, O, S(O)n, N(C(xe2x95x90O)R17), N(R19), C(H)(OR20), NR25, or C(xe2x95x90O);
R8 is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)tR22, xe2x80x94NR6R7, xe2x80x94NR16(CH2)nNR6R7, and xe2x80x94(CH2)kR25,
R9 is C1-C4 alkyl;
R14 and R15 are independently selected at each occurrence from the group consisting of hydrogen, C1-C2 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkyl-alkyl;
R16 is hydrogen;
R1a is C1-C3 alkyl;
R20 is independently selected at each occurrence from the group consisting of hydrogen, C1-C2 alkyl, and C2-C3 alkenyl;
R22 is independently selected at each occurrence from the group consisting of OR24, xe2x80x94S(O)nR19, and xe2x80x94C(xe2x95x90O)R25;
R23 and R24 are independently selected at each occurrence from hydrogen and C1-C2 alkyl;
R25, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, azocinyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl. quinuclidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, triazinyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
R25a, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of H, phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, azocinyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isoindolinyl, isoindolyl, isoquinolinyl, benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, triazinyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
k is 1-3;
p and q are 0-2; and
r is 1-2.
Other more preferred compounds of this invention are those compounds of Formula I wherein, when Y is CR29:
R1 is methyl;
R3 is C1-C2 alkyl, NR6R7, OR8, SR8, C1-C2 alkyl or aryl substituted with R27, halogen, or is N-linked piperidinyl, piperazinyl, morpholino, thiomorpholino, imidazolyl, or is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, where substitution by R27 can occur on any carbon containing substituent;
X is Br, I, S(O)nR8, OR8, NR14R15, or alkyl substituted with R5;
Xxe2x80x2 is hydrogen, Br, I, S(O)nR8, OR8, NR14R15, or alkyl substituted with R5;
R5 is halogen, C1-C2 alkyl, C1-C2 alkoxy, or xe2x80x94NR14R15;
R6 and R7 are independently selected at each occurrence from the group consisting of hydrogen and C1-C2 alkyl, or, when considered with the commonly attached nitrogen, can be taken together to form piperidine, piperazine, morpholine or thiomorpholine;
R8 is independently selected at each occurrence from the group consisting of hydrogen, C1-C2 alkyl, and aryl optionally substituted with 1-2 groups selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, NHC(xe2x95x90O)(C1-C2 alkyl), NH(C1-C2alkyl), and N(C1-C2 alkyl)2;
R14 and R15 are independently selected at each occurrence from the group consisting of hydrogen and C1-C2 alkyl; and
R30 is hydrogen or cyano.
The following compounds are specifically preferred:
N-(2,4-dimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromophenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-methylphenyl)-N-methyl-4-morpholino-6-methyl-2-pyrimidinamine;
N-(2,4-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4-dibromophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-tert-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-tert-butylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-trifluoromethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4,6-trimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4,6-trimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4-morpholino-6-methyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-propyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-cyclohexylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-formyl-piperazino)-6-methyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-trifluoromethyl-2-pyrimidinamine;
N-(2-bromo-4-methoxyethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(2-thiopheno)-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyanomethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-thiomorpholino-6-methyl-2-pyrimidinamine;
N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrmidinamine;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;
N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-dimethylamino-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl -2-pyrimidinamine;
N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-dimethylamino-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4-dimethylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-methylthiomethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl -4-methyl-6-thiomorpholino-2-pyrimidinamine;
N-(2,4-diiodophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4-diiodophenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxyethylamino)-2-pyrimidinamine;
N-(2,6-dimethoxy-4-methylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-iodophenyl)-N-methyl-4,6-diethyl-2-pyrmidinamine;
N-(2-iodophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
4,6-dimethyl-2-(N-(2-bromo-4-(1-methylethyl)phenyl)-N-methylamino)pyridine;
4,6-dimethyl-2-(N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethylamino)pyridine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-2,4-dimethoxy-6-pyrimidinamine;
2,6-dimethyl-4-(N-(2-bromo-4-(1-methylethyl)phenyl)amino)pyridine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-morpholinylcarbonyl)-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(morpholinylmethyl)-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(1-piperidinylcarbonyl)-2-pyrimidinamine;
Methyl-2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidinecarboxylate;
2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-N-cyclohexyl-6-methyl-4-pyrimidinecarboxamide;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1-piperazinylcarbonyl)-2-pyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-1,3,5-triazin-2-amine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
N-ethyl)-N-{2-iodo-4-(1-methylethyl)phenyl}-4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazin-2-amine;
N-ethyl-N-{2-iodo-4-(1-methylethyl)phenyl}-4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
N-ethyl-N-{2 -iodo-4-(1-methylethyl)phenyl}-4-methyl-6-(1-piperidinyl)-1,3,5-triazin-2-amine;
1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-3-cyano-4-phenyl-6-methyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-4-phenyl-6-methyl-7-azaindole;
1-(2-bromo-4,6-dimethoxyphenyl)-1)-3-cyano-4,6-dimethyl-7-azaindole:
1-(2-bromo-4,6-dimethoxyphenyl)-4,6-dimethyl-7-azaindole;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-N,N-diethylamino-6-methyl-1,3,5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4,6-dichloro-1,3,5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4,6-dimethoxy-1,3,5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-imidazolino-6-methyl-1,3,5 triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-morpholino-6-methyl-1,3,5 triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-N,N-dimethylamino-6-methyl-1,3,5 triazin-2-amine;
N-(2,4,6-trimethoxyphenyl)-N-ethyl-4-morpholino-6-methyl-1,3,5 triazin-2-amine,
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-N,N-dimethylamino-6-methyl-1,3,5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-thiozolidino-6-methyl-1,3,5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-benzyloxy-6-methyl-1,3,5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-phenyloxy-6-methyl-1,3,5 triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-{4-(ethylpiperizinoate)}-6-methyl-1,3,5 triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-{4-(piperizinic acid)}-6-methyl-1,3,5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-{3-(malon-2-yldiethyl ester)}-6-methyl-1,3,5-triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-(1-cyano-1-phenylmethyl)-6-methyl-1,3,5 triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-1-methylethyl-4-morpholino-6-methyl-1,3,5 triazin-2-amine;
N-(2-iodo-4-dimethylhydroxymethylphenyl)-N-ethyl-4,6-dichloro-1,3,5 triazin-2-amine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine, S-dioxide;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine, S-oxide;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-benzyloxy-1,3,5 triazin-2-amine;
N-(2-iodo-4-dimethylhydroxymethyl)-N-ethyl-4,6-dichloro-1,3,5 triazin-2-amine;
N-{2-iodo-4-(1-methylethyl)phenyl}-N-allyl-4-morpholino-6-methyl-2-pyrimidinamine;
N-{2-iodo-4-(1-methylethyl)phenyl}-N-ethyl-4-chloro-6-methyl-2-pyrimidinamine;
N-{2-methylthio-4-(1-methylethyl)phenyl}-N-ethyl-4(S)-(N-methyl-2-pyrrolidinomethoxy)-6-methyl-2-pyrimidinamine;
N-{2,6-dibromo-4-(1-methylethyl)phenyl}-4-thiomorpholino-6-methyl-2-pyrimidinamine;
N-{2-methylthio-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{2-methylthio-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{2-methylsulfinyl-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{2-iodo-4-(1-methylethyl)phenyl}-N-ethyl-4-thiazolidino-6-methyl-2-pyrimidinamine;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4,6-dimethyl-2-pyrimidinamino)-2,3,4,5-tetrahydro-4-(1-methylethyl)-1,5-benzothiazepine;
N-{2-methylsulfonyl-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{2-ethylthio-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-ethylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylsulfonyl-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2-pyrimidinamine;
N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{2-methylthio-4-(N-acetyl-N-methylamino)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyirmidinamine;
N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{4-(1-methoxyethyl)-2-methylthiophenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{4-(N-methylamino)-2-methylthiophenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{4-(N,N-dimethylamino)-2-methylthiophenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-formyl-6-methyl-2-pyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-hydroxyethoxymethyl-6-methyl-2-pyrimidinamine;
N-(2-bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(3-bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,3-dibromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,6-dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole;
1-(2-bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole;
1-(2-bromo-4,6-dimethoxyphenyl)-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-6-chloro-3-cyano4-methyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-6-chloro-4-methyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-4-chloro-34yano-methyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole;
N-(2-bromo-6-methoxy-pyridin-3-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(3-bromo-5-methyl-pyridin-2-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(6-methoxy-pyridin-3-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-6-methoxy-pyridin-3-yl)-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5 triazin-2-amine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{N-(2-furylmethyl)-N-methylamino}carbonyl-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{(4,4-ethylenedioxypiperidino)carbonyl}-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(4-oxopiperidino)carbonyl-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(4-oxopiperidino)methyl-6-methylpyrimidinamine, hydrochloride salt;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(imidazol-1-yl)methyl-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{3-(methoxyphenyl)methoxymethyl}-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(2-thiazolyl)carbonyl-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(2-imidazolyl)carbonyl-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(5-indolylcarbonyl)-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(4-fluorophenyl)carbonyl-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-carboxy-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-acetyl-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(hydroxy-3-pyridyl-methyl)-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{4-(methoxyphenyl)-3-pyridyl-hydroxymethyl}-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(3-pyrazolyl)-6-methylpyrimidinamine, hydrochloride salt;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(1-aminoethyl)-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{2-(4-tetrazolyl)-1-methylethyl}-6-methylpyrimidinamine;
2-(N-{2-bromo-4-(2-propyl)phenyl}amino)-4-carbomethoxy-6-methylpyrimidine;
2-(N-{2-bromo-4-(2-propyl)phenyl}-N-ethylamino)-4-carbomethoxy-6-methylpyrimidine;
2-(N-{2-bromo-4-(2-propyl)phenyl}-N-ethylamino)-6-methylpyrimidine-4-morpholinocarbonyl;
9{2-bromo-4-(2-propyl)phenyl}-2-methyl-6-morpholino purine;
9{2-bromo-4-(2-propyl)phenyl}-2-methyl-6-morpholino-8-azapurine;
1{2-bromo-4-(2-propyl)phenyl}-2-methyl-6-morpholino-5,7-diaza-indazole; and
2-(N-{2-bromo-4-(2-propyl)phenyl}-N-ethylamino)-4-(morpholinomethyl)-6-methylpyrimidine.
The above-described compounds and their corresponding salts possess antagonistic activity for the corticotropin releasing factor receptor and can be used for treating affective disorders, anxiety, depression, irritable bowel syndrome, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems in mammals.
Further included in this invention is a method of treating affective disorders, anxiety, depression, irritable bowel syndrome, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems in mammals in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of formula (I): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is CR3a,
N, or CR29;
when Y is CR3a or N:
R1 is independently selected at each occurrence from the group consisting of C1-C4 alkyl, halogen, C1-C2 haloalkyl, NR6R7, OR8, and S(O)nR8;
R3 is C1-C4 alkyl, aryl, C3-C6 cycloalkyl, C1-C2 haloalkyl, halogen, nitro, NR6R7, OR8, S(O)nR8, C(xe2x95x90O)R9, C(xe2x95x90O)NR6R7, C(xe2x95x90S)NR6R7, xe2x80x94(CHR16)kNR6R7, (CH2)kOR8, C(xe2x95x90O)NR10CH(R11)CO2R12, xe2x80x94C(OH)(R25)(R25a), xe2x80x94(CH2)pS(O)n-alkyl, xe2x80x94(CHR16)R25, xe2x80x94C(CN)(R25)(R16) provided that R25 is not xe2x80x94NHxe2x80x94 containing rings, xe2x80x94C(xe2x95x90O)R25, xe2x80x94CH(CO2R16)2, NR10C(xe2x95x90O)CH(R11)NR10R12, NR10CH(R11)CO2R12; substituted C1-C4 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, substituted C1-C4 alkoxy, aryl-(substituted C1-C4) alkyl, aryl-(substituted C1-C4) alkoxy, substituted C3-C6 cycloalkyl, amino-(substituted C1-C4) alkyl, substituted C1-C4 alkylamino, where substitution by R27 can occur on any carbon containing substituent; 2-pyridinyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl, phenyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, imidazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl; or 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
J, K, and L are independently selected at each occurrence from the group of
N, CH, and CXxe2x80x2;
M is CR5 or N;
V is CR1a or N;
Z is CR2 or N;
R1a, R2, and R3a are independently selected at each occurrence from the group consisting of hydrogen, halo, halomethyl, C1-C3 alkyl, and cyano;
R4 is (CH2)mOR16, C1-C4 alkyl, allyl, propargyl, (CH2)mR13, or xe2x80x94(CH2)mOC(O)R16;
X is halogen, S(O)2R8, SR8, halomethyl, xe2x80x94(CH2)pOR8, xe2x80x94OR8, cyano, xe2x80x94(CHR16)pNR14R15, xe2x80x94C(xe2x95x90O)R8, C1-C6 alkyl, C4-C10 cycloalkylalkyl, C1-C10alkenyl, C2-C10alkynyl, C1-C10alkoxy, aryl-(C2-C10)-alkyl, C3-C6 cycloalkyl, aryl-(C1-C10)-alkoxy, nitro, thio-(C1-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, xe2x80x94C(xe2x95x90NOR16)H, or xe2x80x94C(xe2x95x90O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;
Xxe2x80x2 is independently selected at each occurrence from the group consisting of hydrogen, halogen, S(O)nR8, halomethyl, xe2x80x94(CHR16)pOR8, cyano, xe2x80x94(CHR16)pNR14R15, C(xe2x95x90O)R8, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, aryl-(C1-C10)-alkyl, C3-C6 cycloalkyl, aryl-(C1-C10)-alkoxy, nitro, thio-(C1-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, xe2x80x94C(xe2x95x90NOR16)H, and xe2x80x94C(xe2x95x90O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;
R5 is halo, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-4-alkyl, C1-C6 alkyl, C1-C3 haloalkyl, xe2x80x94(CHR16)pOR8, xe2x80x94(CHR16)pS(O)nR8, xe2x80x94(CHR16)pNR14R15, C3-C6cycloalkyl, C2-C10alkenyl, C1-C10 alkynyl, aryl-(C2-C10)-akyl, aryl-(C1-C10)-alkoxy, cyano, C3-C6 cycloalkoxy, nitro, amino-(C2-C10)-alkyl, thio-(C2-C10)-alkyl, SOn(R8), C(xe2x95x90O)R8, xe2x80x94C(xe2x95x90NOR16)H, or xe2x80x94C(xe2x95x90O)NR14R15, where substitution by R18 can occur on any carbon containing substituents;
R6 and R7 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, (C4-C12)-cycloalkylalkyl, xe2x80x94(CH2)kR13, (CHR16)pOR8, xe2x80x94(C1-C6 alkyl)-aryl, heteroaryl, aryl, xe2x80x94S(O)n-aryl or xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl wherein the aryl or heteroaryl groups are optionally substituted with 1-3 groups selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, nitro, carboxy, CO2(C1-C6 alkyl), cyano, and S(O)zxe2x80x94(C1-C6-alkyl); or can be taken together to form xe2x80x94(CH2)qA(CH2)rxe2x80x94, optionally substituted with 0-3 R17; or, when considered with the commonly attached nitrogen, can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-3 groups consisting of hydrogen, C1-C6 alkyl, hydroxy, or C1-C6 alkoxy;
A is CH2, O, NR25, C(xe2x95x90O), S(O)n, N(C(xe2x95x90O)R17), N(R19), C(H)(NR14R15), C(H)(OR20), C(H)(C(xe2x95x90O)R21), or N(S(O)nR21);
R8 is independently selected at each occurrence from the group consisting of hydrogen; C1-C6 alkyl; xe2x80x94(C4-C12) cycloalkylalkyl; (CH2)nR22; C3-C10 cycloalkyl; xe2x80x94NR6R7; aryl; xe2x80x94NR16(CH2)nNR6R7; xe2x80x94(CH2)kR25; and (CH2)theteroaryl or (CH2)taryl, either of which can optionally be substituted with 1-3 groups selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, nitro, carboxy, CO2(C1-C6 alkyl), cyano, and S(O)z(C1-C6-alkyl);
R9 is independently selected at each occurrence from R10, hydroxy, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkenyl, aryl substituted with 0-3 R18, and xe2x80x94(C1-C6 alkyl)-aryl substituted with 0-3 R18;
R10, R16, R23, and R24 are independently selected at each occurrence from hydrogen or C1-C4 alkyl;
R11 is C1-C4 alkyl substituted with 0-3 groups chosen from the following: keto, amino, sulfhydryl, hydroxyl, guanidinyl, p-hydroxyphenyl, imidazolyl, phenyl, indolyl, indolinyl, or, when taken together with an adjacent R10, are (CH2)t;
R12 is hydrogen or an appropriate amine protecting group for nitrogen or an appropriate carboxylic acid protecting group for carboxyl;
R13 is independently selected at each occurrence from the group consisting of CN, OR19, SR19, and C3-C6 cycloalkyl;
R14 and R15 are independently selected at each occurrence from the group consisting of hydrogen, C4-C10 cycloalkyl-alkyl, and R19;
R17 is independently selected at each occurrence from the group consisting of R10, C1-C4 alkoxy, halo, OR23, SR23, NR23R24, and (C1-C6) alkyl (C1-C4) alkoxy;
R18 is independently selected at each occurrence from the group consisting of R10, hydroxy, halogen, C1-C2 haloalkyl, C1-C4 alkoxy, C(xe2x95x90O)R24, and cyano;
R19 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)wR22, and aryl substituted with 0-3 R18;
R20 is independently selected at each occurrence from the group consisting of R10, C(xe2x95x90O)R31, and C2-C4 alkenyl;
R21 is independently selected at each occurrence from the group consisting of R10, C1-C4xe2x88x92 alkoxy, NR23R24, and hydroxyl;
R22 is independently selected at each occurrence from the group consisting of cyano, OR24, SR24, NR23R24, C1-C6 alkyl, C3-C6 cycloalkyl, xe2x80x94S(O)nR31, and xe2x80x94C(xe2x95x90O)R25;
R25, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, xcex2-carbolinyl, tetrahydrofuranyl, tetrazolyl, thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which can be substituted with 0-3 groups chosen from keto and C1-C4 alkyl;
R25a, which can be optionally substituted with 0-3 R17, is independently selected at each occurrence from the group consisting of H and R25;
R27 is independently selected at each occurrence from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 alkoxy, aryl, nitro, cyano, halogen, aryloxy, and heterocycle optionally linked through O;
R31 is independently selected at each occurrence from the group consisting of C1-C4 alkyl, C3-C7 cycloalkyl, C4-C10 cycloalkyl-alkyl, and aryl-(C1-C4) alkyl;
k, m, and r are independently selected at each occurrence from 1-4;
n is independently selected at each occurrence from 0-2;
p, q, and z are independently selected at each occurrence from 0-3;
t and w are independently selected at each occurrence from 1-6,
provided that when J is CXxe2x80x2 and K and L are both CH, and M is CR5, then
(A) when V and Y are N and Z is CH and R1 and R3 are methyl,
(1) and R4 is methyl, then
(a) R5 can not be methyl when X is OH and Xxe2x80x2 is H;
(b) R5 can not be xe2x80x94NHCH3 or xe2x80x94N(CH3)2 when X and Xxe2x80x2 are xe2x80x94OCH3; and
(c) R5 can not be -N(CH3)2 when X and Xxe2x80x2 are xe2x80x94OCH2CH3;
(2) and R4 is ethyl, then
(a) then R5 can not be methylamine when X and Xxe2x80x2 are xe2x80x94OCH3;
(b) R5 can not be OH when X is Br and Xxe2x80x2 is OH; and
(c) R5 can not be xe2x80x94CH2OH or xe2x80x94CH2N(CH3)2 when X is xe2x80x94SCH3 and Xxe2x80x2 is H;
(B) when V and Y are N, Z is CH, R4 is ethyl, R5 is iso-propyl, X is Br, Xxe2x80x2 is H, and
(1) R1 is CH3, then
(a) R3 can not be OH, piperazin-1-yl, xe2x80x94CH2-piperidin-1-yl, xe2x80x94CH2-(N-4-methylpiperazin- 1-yl), xe2x80x94C(O)NH-phenyl, xe2x80x94CO2H, xe2x80x94CH2O-(4-pyridyl), xe2x80x94C(O)NH2, 2-indolyl, xe2x80x94CH2O-(4-carboxyphenyl), xe2x80x94N(CH2CH3)(2-bromo-4-isopropylphenyl);
(2) R1 is xe2x80x94CH2CH2CH3 then R3 can not be xe2x80x94CH2CH2CH3;
(C) when V, Y and Z are N, R4 is ethyl, and
(1) R5 is iso-propyl, X is bromo, and Xxe2x80x2 is H, then
(a) R3 can not be OH or xe2x80x94OCH2CN when R1 is CH3; and
(b) R3 can not be xe2x80x94N(CH3)2 when R1 is xe2x80x94N(CH3)2;
(2) R5 is xe2x80x94OCHxe2x80x94, X is xe2x80x94OCH3, and Xxe2x80x2 is H, then R3 and R1 can not both be chloro;
further provided that when J, K, and L are all CH and M is CR5, then
(D) at least one of V, Y, and Z must be N;
(E) when V is CR1a, Z and Y can not both be N;
(F) when Y is CR3a, Z and V can not both be N;
(G) when Z is CR2, V and Y must both be N;
(H) Z can be N only when both V and Y are N or when V is CR1a and Y is CR3a;
(I) when V and Y are N, Z is CR2, and R2 is H or C1-C3 alkyl, and R4 is C1-C3 alkyl, R3 can not be 2-pyridinyl, indolyl, indolinyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-phenothiazinyl, or 4-pyrazinyl;
(J) when V and Y are N; Z is CR2; R2 is H or C1-C3 alkyl; R4 is C1-C4 alkyl; R5, X, and/or Xxe2x80x2 are OH, halo, CF3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, cyano, amino, carbamoyl, or C1-C4 alkanoyl; and R1 is C1-C4 alkyl, then R3 can not be xe2x80x94NH(substituted phenyl) or xe2x80x94N(C1-C4 alkyl)(substituted phenyl);
and wherein, when Y is CR29:
J, K, L, M, Z, A, k, m, n, p, q, r, t, w, R3, R10, R11, R12, R13, R16, R18, R19, R21, R23, R24, R25, and R27 are as defined above and R25a, in addition to being as defined above, can also be C1-C4 alkyl, but
V is N;
R1 is C1-C2 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 alkoxy, halogen, amino, methylamino, dimethylamino, aminomethyl, or N-methylaminomethyl;
R2 is independently selected at each occurrence from the group consisting of hydrogen, halo, C1-C3 alkyl, nitro, amino, and xe2x80x94CO2R10;
R4 is taken together with R29 to form a 5-membered ring and is xe2x80x94C(R28)xe2x95x90 or xe2x80x94Nxe2x95x90 when R29 is xe2x80x94C(R30)xe2x95x90 or xe2x80x94Nxe2x95x90, or xe2x80x94CH(R28)xe2x80x94 when R29 is
X is Cl, Br, I, S(O)nR8, OR8, halomethyl, xe2x80x94(CHR16)pOR8, cyano, xe2x80x94(CHR16)pNR14R15, C(xe2x95x90O)R8, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, aryl-(C1-C10)-alkyl, C3-C6 cycloalkyl, aryl-(C1-C10 )-alkoxy, nitro, thio-(C1-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16)xe2x80x94C1-C4-alkyl, -C(xe2x95x90NOR16)H, or C(xe2x95x90O)NR14R15 where substitution by R18 can occur on any carbon containing substituents;
Xxe2x80x2 is hydrogen, Cl, Br, I, S(O)nR8, xe2x80x94(CHR16)pOR8, halomethyl, cyano, xe2x80x94(CHR16)pNR14R15, C(xe2x95x90O)R8, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10, alkoxy, aryl-(C1-C10)-alkyl, C3-C6 cycloalkyl, aryl-(C2-C10)-alkoxy, nitro, thio-(C2-C10)-alkyl, xe2x80x94C(xe2x95x90NOR16)-C1-C4-alkyl, xe2x80x94C(xe2x95x90NOR16)H, or C(xe2x95x90O)NR8R15 where substitution by R18 can occur on any carbon containing substituents;
R5 is halo, xe2x80x94C(xe2x95x90NOR16)-C1-C4-alkyl, C1-C6 alkyl, C1-C3 haloalkyl, C1-C6 alkoxy, (CHR16)pOR8, (CHR16)pS(O)nR8, (CHR16)pNR14R15, C3-C6 cycloalkyl, C1-C10 alkenyl, C2-C10 alkynyl, aryl-(C2-C10)-alkyl, aryl-(C1-C10)-alkoxy, cyano, C3-C6 cycloalkoxy, nitro, amino-(C1-C10)-alkyl, thio-(C1-C10)-alkyl, SOn(R8), C(xe2x95x90O)R8, xe2x80x94C(xe2x95x90NOR16)H, or C(xe2x95x90O)NR8R15 where substitution by R18 can occur on any carbon containing substituents;
R6 and R7 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)kR13, (C4-C12)-cycloalkylalkyl, C1-C6 alkoxy, xe2x80x94(C1-C6 alkyl)-aryl, heteroaryl, aryl, xe2x80x94S(O)z-aryl or xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl wherein the aryl or heteroaryl groups are optionally substituted with 1-3 groups selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl), nitro, carboxy, CO2(C1-C6 alkyl), and cyano; or can be taken together to form xe2x80x94(CH2)qA(CH2)rxe2x80x94, optionally substituted with 0-3 R17; or, when considered with the commonly attached nitrogen, can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-3 groups consisting of hydrogen, C1-C6 alkyl, hydroxy, or C1-C6 alkoxy;
R8 is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, xe2x80x94(C4-C12) cycloalkylalkyl, (CH2)tR22, C3-C10 cycloalkyl, xe2x80x94(C1-C6 alkyl)-aryl, heteroaryl, xe2x80x94NR16, xe2x80x94N(CH2)nNR6R7; xe2x80x94(CH2)kR25, xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, NHC(xe2x95x90O)(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)2, nitro, carboxy, CO2(C1-C6 alkyl), and cyano;
R9 is independently selected at each occurrence from R2, hydroxy, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, and aryl substituted with 0-3 R18;
R14 and R15 are independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)tR22, and aryl substituted with 0-3 R18;
R17 is independently selected at each occurrence from the group consisting of R10, C1-C4 alkoxy, halo, OR23, SR23, and NR23R24;
R20 is independently selected at each occurrence from the group consisting of R10 and C(xe2x95x90O)R31;
R22 is independently selected at each occurrence from the group consisting of cyano, R24, SR24, NR23R24, C3-C6 cycloalkyl, xe2x80x94S(O)nR31, and xe2x80x94C(xe2x95x90O)R25;
R26 is hydrogen or halogen:
R28 is C1-C2 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, hydrogen, C1-C2 alkoxy, halogen, or C2-C4 alkylamino; R29 is taken together with R4 to form a five membered ring and is: xe2x80x94CH(R30)xe2x80x94 when R4 is xe2x80x94CH(R28)xe2x80x94, xe2x80x94C(R30)xe2x95x90 or xe2x80x94Nxe2x95x90 when R4 is xe2x80x94C(R28)xe2x95x90 or xe2x80x94Nxe2x95x90;
R30 is hydrogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, halogen, C1-C2 alkenyl, nitro, amido, carboxy, or amino;
R31 is C1-C4 alkyl, C3-C7 cycloalkyl, or aryl-(C1-C4) alkyl;
provided that when J, K, and L are all CH, M is CR5, Z is CH, R3 is CH3,
R28 is H, R5 is iso-propyl, X is Br, Xxe2x80x2 is H, and R1 is CH3, then R30 can not be H, xe2x80x94CO2H, or xe2x80x94CH2NH2;
and further provided that when J, K and L are all CH; M is CR5; Z is N; and
(A) R29 is xe2x80x94C(R1)xe2x95x90; then one of R28 or R30 is hydrogen;
(B) R29 is N; then R3 is not halo, NH2, NO2, CF3, CO2H, CO2-alkyl, alkyl, acyl, alkoxy, OH, or xe2x80x94(CH2)mOalkyl;
(C) R29 is N; then R28 is not methyl if X or Xxe2x80x2 are bromo or methyl and R5 is nitro; or
(D) R29 is N, and R1 is CH3 and R3 is amino; then R5 is not halogen or methyl.
Further included in this invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and therapeutically effective amount of any one of the above-described compounds.
The compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor. These would be provided in commercial kits comprising a compound provided by this invention.
In the present invention it has been discovered that the provided compounds useful as antagonists of Cortocotropin Releasing Factor and for the treatment of effective disorders, anxiety, or depression.
The present invention also provides methods for the treatment of effective disorder, anxiety or depression by administering to a host a therapeutically effective amount of a compound of formula (I) as described above. By therapeutically effective amount is meant an amount of a compound of the present invention effective to antagonize abnormal levels of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
The compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compound described herein, and all such stable isomers are comtemplated in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. Also, it is realized that cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomers forms. All chiral, diastereomeric, and racemic forms and all geometric isomers forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (for example, R1 through R10, m, n, A, w, Z, etc.) occurs more than one time in any constituent or in formula (I) or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, in xe2x80x94NR8R9, each of the substituents may be independently selected from the list of possible R8 and R9 groups defined. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur at any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur at any stable point along the chain, such as ethynyl, propynyl and the like. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean phenyl, biphenyl or naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d is meant to include unsubstituted, monosubstituted or disubstituted 5-, 6- or 10-membered mono- or bicyclic aromatic rings, which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N, and S and are expected to be active. Included in the definition of the group heteroaryl, but not limited thereto, are the following: 2-, or 3-, or 4-pyridyl; 2- or 3-furyl; 2- or 3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3-indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl; 2- or 4- or 5-imidazolyl; 1- or 2- benzimidazolyl; 2- or 4- or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4- cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or 2-quinoxalinyl ring. Particularly preferred are 2-, 3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl; or 1-, 3-, or 4-isoquinolinyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H- 1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrole, imidazolyl, pyrazolyl, isothiazolyl, isoxazole, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindole, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that one or more hydrogens of the designated moiety is replaced with a selection from the indicated group, provided that no atom""s normal valency is exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens attached to an atom of the moiety are replaced.
By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
As used herein, the term xe2x80x9cappropriate amino acid protecting groupxe2x80x9d means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids, modified and unusual amino acids, as well as amino acids that are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as, those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. Modified or unusual amino acids that can be used in the practice of the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, xcex2-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The term xe2x80x9camino acid residuexe2x80x9d as used herein means that portion of an amino acid (as defined herein) that is present in a peptide.
The term xe2x80x9cpeptidexe2x80x9d as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond. The term xe2x80x9cpeptidexe2x80x9d also includes compounds containing both peptide and non-peptide components, such as pseudopeptide or peptide mimetic residues or other non-amino acid components. Such a compound containing both peptide and non-peptide components may also be referred to as a xe2x80x9cpeptide analogxe2x80x9d.
The term xe2x80x9cpeptide bondxe2x80x9d means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making acid or base salts of the compound of formula (I). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers that release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of formula (I) wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I); and the like.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa. (1985), p. 1418, the disclosure of which is hereby incorporated by reference.
The novel substituted-2-pyridinamines, substituted triazines, substituted pyridines and substituted anilines of the present invention can be prepared by one of the general schemes outlined below (Scheme 1-23).
Compounds of the Formula (I), wherein Z is CR2 and J is CXxe2x80x2 and K and L are both CH, can be prepared as shown in Scheme 1. 2-Hydroxy-4,6-dialkylpyrimidine (II) was converted to the corresponding derivative (III) with an appropriate leaving group in the 2-position such as, but not limited to, Cl, Br, SO2CH3, OSO2CH3, or OSO2C6H4xe2x80x94CH3, or SCH3 by treatment with phosphorous oxychloride (POCl3), phosphorous oxybromide (POBr3), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), or sodium thiomethoxide optionally followed by oxidation with hydrogen peroxide, chlorine gas, or an organic peracid, such as, m-chloroperbenzoic 
acid, respectively. This derivative was reacted with the appropriate 2,4-substituted aniline (IV) in a high boiling solvent, such as, but not limited to, ethylene glycol, methoxyethoxyethanol etc., or in an aprotic solvent such as tetrahydrofuran, dioxane, toluene, xylene, or N,N-dimethyformamide, facilitated by the optional use of a base such as sodium hydride (NaH), lithium diisopropylamide (LDA), which are preferred. The coupled product (V) was treated with a base such as NaH or LDA in an aprotic solvent such as tetrahydrofuran (THF) or N,N-dimethylformamide (DMF) or in a combination of potassium tert-butoxide in t-butanol (tBuOK/tBuOH) followed by an alkylating agent R4Lxe2x80x2, such as an alkyl iodide, mesylate or tosylate to afford the corresponding alkylated product of Formula (I).
The compounds of Formula (I), wherein V and Y are N and Z, J, K, and L are all CH, can be prepared as shown in Scheme 2. The substituted aniline (VI) was converted to the corresponding guanidinium salt (VII) by treatment with the appropriate reagent such as cyanamide. 
The guanidinium salt (VII) was reacted with a xcex2-diketone (VIII) in the presence of a base such as potassium carbonate (K2CO3) in N,N-dimethylformamide (DMF) or in an alcoholic solvent in the presence of the corresponding alkoxide to afford the corresponding pyrimidine (IX). This was subsequently alkylated to provide (X), a compound of Formula (I) wherein Xxe2x80x2 is hydrogen, by conditions identical to those described in Scheme 1.
Compounds of the Formula (I), wherein V and Y are N and Z, J, K, and L are all CH and R3 is NR6R7, can be prepared as shown in Scheme 3. Treatment of 2,4-dichloro-6-alkylpyrimidine (XI) with a primary or secondary amine in the presence of a non-nucleophilic base such as a trialkylamine afforded selectively the corresponding 4-substituted amino adduct (XII). 
This in turn, was reacted with the substituted aniline (IV) under conditions identical to those described in Scheme 1 to afford the corresponding secondary pyrimidinamine (XIII). This was alkylated under conditions described in Schemes 1 and 2. 
Compounds of Formula (I) wherein J, K, and L are CH and Z is CR2 and V and Y are N can also be prepared by the route outlined in Scheme 4. The guanidinium salt (XII) was reacted with a xcex2-ketoester (XV) in the presence of a base such as an alkoxide in the corresponding alcoholic solvent to give the adduct (XVI). Treatment of the hydroxy group in (XVI) with either phosphorous oxychloride, phosphorous oxybromide, methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride provided (XVII), wherein the L is a leaving group and is, respectively, Cl, Br, I, OMs, OTs, or OTf. The L group of (XVII) was displaced with a nucleophile such as NR6R7, OR6, SR6, CN, an organolithium, organomagnesium, organosodium, organopotassium, an alkyl cuprate, or in general an organometallic reagent to the corresponding adduct (IX), which was further alkylated under the standard conditions to produce (XVIII).
Compounds of the Formula (I) that are substituted at the 2-position of the phenyl ring could be prepared as outlined in Scheme 5. 
Compounds of the Formula (I) wherein X is other than bromine can be prepared by the intermediates shown in Scheme 5. Reaction of the 2-halo compound (V) wherein X is bromine or hydrogen with a metalating agent such as, but not limited to, n-BuLi or t-BuLi in an aprotic solvent, preferably ether or tetrahydrofuran, provided the corresponding 2-lithio intermediate (X=Li, not isolated) which was further reacted with an electrophile such as iodine or trimethyltin chloride ((CH3)3SnCl) to give the corresponding 2-substituted product (XIX). These intermediates can also be further reacted using palladium-catalyzed coupling reactions well known to one of skill in the art to prepare the compounds of the invention.
Compounds of the Formula (I) wherein Z, K and L are all CHI, J is N or CH, and Rxe2x80x2 is ethyl can be prepared as illustrated in Scheme 6. Sequential addition/re-oxidation of an alkyllithium to 2-chloropyrimidine can provide intermediate (XXII) wherein the R1 and R3 can be independent of one another. Displacement of the chlorine by a suitable nitrogen nucleophile such as an aniline under similar conditions of Scheme 1, followed by attachment of the R4 group by alkylation in an analogous method of Schemes 1 or 2 can provide the compounds of the invention. 
Compounds of the Formula (I) wherein Z is N can be prepared according to the method outlined in Scheme 7. Known triazine (XXIII), synthesis of which is reported in J. Amer. Chem. Soc. 77:2447 (1956), can be reacted with a substituted aniline (IV) in a analogous manner to Scheme 1. Similarly, the 2,4 dichloro 6-methyltriazine, which can be prepared via the method reported in U.S. Pat. No. 3,947,374 can be coupled to the substituted aniline (IV) to provide (XXIV) where R3 is chlorine. Nucleophilic addition in protic or aprotic solvents allows for a variety of substituents at this position (XXV). Alkylation of the secondary amine as previously described provide triazine compounds of formula (I). 
Compounds wherein R3 is carboxy-derived are synthesized according to Scheme 8. A pyrimidine ester of formula (XXVI), which is prepared by the literature method reported in Budesinsky and Roubinek, Collection. Czech. Chem. Comm. 26:2871-2885 (1961) is reacted with an amine of formula (IV) in the presence of an inert solvent to afford an intermediate of formula (XXVII). Inert solvents include lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons (preferably dioxane), dialkylformamides (preferably N,N-dimethylformamide), dialkylacetamides, (preferably N,N-dimethylacetamide), cyclic amides, (preferably N-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethyl sulfoxide), hydrocarbons of 5 to 10 carbons or aromatic hydrocarbons of 6 to carbons. Compounds of formula (XXVII) are treated with a base and a compound of Formula R4X, where X is halogen (preferably Cl, Br or I) in an inert solvent. Such bases include a tertiary amine, an alkali metal hydride 
(preferably sodium hydride), an aromatic amine (preferably pyridine), or an alkali metal carbonate or alkoxide. The choice of inert solvent must be compatible with the choice of base (see J. March, Advanced Organic Chemistry (New York: J. Wiley and Sons, 1985) pp. 364-366, 412; H. O. House, Modern Synthetic Reactions (New York: W. A. Benjamin Inc., 1972, pp. 510-536)). Solvents include lower alkyl alcohols of 1 to 6 carbons, lower alkanenitriles (preferably acetonitrile), dialkyl ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons (preferably tetrahydrofuran or dioxane), dialkylformamides (preferably N,N-dimethylformamide), cyclic amides, (preferably N-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethyl sulfoxide), hydrocarbons of 5 to 10 carbons or aromatic hydrocarbons to 6 to 10 carbons. Esters of formula (XXVIII) may be converted to acids of formula (XXIX) by acidic or basic hydrolysis (cf. J. March, Advanced Organic Chemistry (New York: J. Wiley and Sons, 1985) pp. 334-338) or by treatment with an alkali metal salt (preferably LiI or NaCN) in the presence of an inert solvent at temperatures ranging from 50 to 200xc2x0 C. (preferably 100 to 180xc2x0 C.) (cf. McMurray, J. E. Organic Reactions, Dauben, W. G. et al., eds., J. Wiley and Sons, New York (1976), Vol. 24, pp. 187-224). Inert solvents include dialkylformamides (preferably N,N-dimethylformamide), dialkylacetamides, (preferably N,N-dimethylacetamide), cyclic amides, (preferably N-methylpyrrolidinone), and dialkyl sulfoxides (preferably dimethyl sulfoxide), or aromatic amines (preferably pyridine). Acids of formula (XXIX) may be treated with a halogenating agent to give an acid halide, which may or may not be isolated, then reacted with an amine of formula HNR6R7, with or without an inert solvent, with or without a base, as taught by the literature (J. March, Advanced Organic Chemistry, J. Wiley and Sons, New York (1985), pp. 370-373, 389), to provide amides of formula (XXX). Halogenating agents include thionyl chloride (SOCl2), oxalyl chloride ((COCl)2), phosphorous trichloride (PCl3), phosphorous pentachloride (PCl5), or phosphorous oxychloride (POCl3). Inert solvents include lower halocarbons of 1 to 6 carbons and 2 to 6 halogens (preferably dichloromethane or dichloroethane), dialkyl ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons (preferably dioxane) or aromatic hydrocarbons to 6 to 10 carbons. Bases include trialkyl amines or aromatic amines (preferably pyridine). Alternatively, esters of formula (XXVIII) may be reacted with an amine of formula HNR6R7, with or without an inert solvent, with or without a base, as taught by the literature (cf. J. March, Advanced Organic Chemistry (New York: J. Wiley and Sons, 1985) pp. 370-373, 389) to generate amides of formula (XXX). Solvents include lower alkyl alcohols of 1 to 6 carbons, lower alkanenitriles (preferably acetonitrile), dialkyl ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons (preferably tetrahydrofuran or dioxane), dialkylformamides (preferably N,N-dimethylformamide), dialkylacetamides, (preferably N,N-dimethylacetamide), cyclic amides, (preferably N-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethyl sulfoxide), hydrocarbons of 5 to 10 carbons or aromatic hydrocarbons to 6 to 10 carbons. Such bases include a tertiary amine, an alkali metal hydride (preferably sodium hydride), an aromatic amine (preferably pyridine), or an alkali metal carbonate or alkoxide. Amides of formula (XXX) may be treated with a reducing agent in an inert solvent to provide amines of formula (XXXI). Such reducing agents include, but are not limited to, alkali metal aluminum hydrides, preferably lithium aluminum hydride, alkali metal borohydrides (preferably lithium borohydride), alkali metal trialkoxyaluminum hydrides (such as lithium tri-t-butoxyaluminum hydride), dialkylaluminum hydrides (such as di-isobutylaluminum hydride), borane, dialkylboranes (such as di-isoamyl borane), alkali metal trialkylboron hydrides (such as lithium triethylboron hydride). Inert solvents include lower alkyl alcohols of 1 to 6 carbons, ethereal solvents (such as diethyl ether or tetrahydrofuran), aromatic or non-aromatic hydrocarbons of 6 to 10 carbons. Reaction temperatures for the reduction range from about xe2x88x9278xc2x0 to 200xc2x0 C., preferably about 50xc2x0 to 120xc2x0 C. The choice of reducing agent and solvent is known to those skilled in the art as taught in the above cited March reference (pp. 1093-1110).
Scheme 9 depicts the synthesis and chemical modifications to form compounds of formula (XXXIII). Esters of formula (XXVIII) or acids of formula (XXIX) may be treated with a reducing agent in an inert solvent to provide alcohols of formula (XXXII). Such reducing agents include, but are not limited to, alkali metal aluminum hydrides, preferably lithium aluminum hydride, alkali metal borohydrides (preferably lithium borohydride), alkali metal trialkoxyaluminum hydrides (such as lithium tri-t-butoxyaluminum hydride), dialkylaluminum hydrides (such as di-isobutylaluminum hydride), borane, dialkylboranes (such as di-isoamyl borane), alkali metal trialkylboron hydrides (such as lithium triethylboron hydride). Inert solvents include lower alkyl alcohols of 1 to 6 carbons, ethereal solvents (such as diethyl ether or tetrahydrofuran), aromatic or non-aromatic hydrocarbons of 6 to 10 carbons. Reaction temperatures for the reduction range from about xe2x88x9278xc2x0 to 200xc2x0 C., preferably about 50xc2x0 to 120xc2x0 C. The choice of reducing agent and solvent is known to those skilled in the art as taught in the above cited March reference (pp. 1093-1110). Alcohols of Formula (XXXII) may be converted to ethers of formula (XXXIII) by treatment with a base and a compound of Formula R8X, where X is halogen. Bases which may be used for this reaction include, but are not limited to, alkali metal hydrides, preferably sodium hydride, alkali metal carbonates, preferably potassium carbonate, alkali metal dialkylamides, preferably lithium di-isopropylamide, alkali metal bis-(trialkylsilyl)amides, preferably sodium bis-(trimethylsilyl)amide, alkyl alkali metal compounds (such as butyl lithium), alkali metal alkoxides (such as sodium ethoxide), alkyl alkaline earth metal halides (such as methyl magnesium bromide), trialkylamines (such as triethylamine or di-isopropylethylamine), polycyclic di-amines (such as 1,4 diazabicyclo[2.2.2]octane or 1,8-diazabicyclo-[5.4.0]undecene) or quaternary ammonium salts (such as Triton B). The choice of inert solvent must be compatible with the choice of base (J. March, Advanced Organic Chemistry (New York: J. Wiley and Sons, 1985) pp. 255-446; H. O. House, Modern Synthetic Reactions (New York: 
W. A. Benjamin Inc., 1972, pp. 546-553)). Solvents include lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons, preferably tetrahydrofuran or dioxane, dialkylformamides, preferably N,N-dimethylformamide, dialkylacetamides, preferably N,N-dimethylacetamide, cyclic amides, preferably N-methylpyrrolidinone, hydrocarbons of 5 to 10 carbons or aromatic hydrocarbons to 6 to 10 carbons.
Alternatively, compounds of formula (XXXII) may be converted to compounds of formula (XXXIV), where Y is halide, arylsulfonyloxy (preferably p-toluenesulfonyloxy), alkylsulfonyloxy (such as methanesulfonyloxy), haloalkylsulfonyloxy (preferably trifluoromethyl-sulfonyloxy), by reaction with a halogenating agent or a sulfonylating agent. Examples of halogenating agents include, but are not limited to, SOCl2, PCl3, PCl3, POCl3, Ph3Pxe2x80x94CCl4, Ph3Pxe2x80x94CBr4, Ph3Pxe2x80x94Br2, Ph3Pxe2x80x94I2, PBr3, PBr5. The choice of halogenating agents and reaction conditions are known to those skilled in the prior art (March reference, pp. 382-384). Sulfonylating agents include, but are not limited to, (lower alkyl)sulfonyl chlorides (preferably methanesulfonyl chloride), (lower haloalkyl) sulfonic anhydrides (preferably trifluoromethylsulfonic anhydride, phenyl or alkyl substituted-phenyl sulfonyl chlorides (preferably p-toluenesulfonyl chloride). The sulfonylation or halogenations may require a base as taught by the literature (March reference, pp. 1172, 382-384). Such bases include a tertiary amine, an alkali metal hydride (preferably sodium hydride), an aromatic amine (preferably pyridine), or an alkali metal carbonate or alkoxide. Solvents for the halogenation or sulfonylation should be inert under the reaction conditions as taught by the literature. Such solvents include lower halocarbons (preferably dichloromethane or dichloroethane), or ethereal solvents (preferably tetrahydrofuran or dioxane). Intermediates of formula (XXXIV) may then be converted to compounds of formula (XXXIII) by treatment with a compound of formula R8OH with or without a base, in an inert solvent (March reference, pp. 342-343). Such bases include alkali metal hydrides, preferably sodium hydride, alkali metal carbonates, preferably potassium carbonate, alkali metal dialkylamides, preferably lithium diiisopropylamide, alkali metal bis-(trialkylsilyl)amides, preferably sodium bis-(trimethylsilyl)amide, alkyl alkali metal compounds (such as n-butyllithium), alkali metal alkoxides (such as sodium ethoxide), alkyl alkaline earth metal halides (such as methyl magnesium bromide), trialkylamines (such as triethylamine or di-isopropylethylamine), polycyclic diamines (such as 1,4 diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undecene) or quaternary ammonium salts (such as Triton B). Solvents include lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons, preferably tetrahydrofuran or dioxane, dialkylformamides, preferably N,N-dimethylformamide, dialkylacetamides, preferably N,N-dimethylacetamide, cyclic amides, preferably N-methylpyrrolidinone, hydrocarbons of 5 to 10 carbons or aromatic hydrocarbons to 6 to 10 carbons.
Intermediates of formula (XXXIII) may be prepared from intermediates of formula (XXXII) by reaction with a triarylphosphine (preferably triphenylphosphine), a di-(lower alkyl) azodicarboxylate) and a compound of formula R8OH in the presence of an inert solvent as described in the general literature (Mitsunobu, O., Synthesis 1:1-28 (1981)).
Compounds of formula (XXXI) may be prepared by treatment of a compound of formula (XXXIV) with a compound of Formula HNR6R7, with or without a base, in an inert solvent (Scheme 9). Such bases and inert solvents may be the same ones used for the transformation of compounds (XXVIII) to compounds (XXX) in Scheme 8.
Compounds of Formula (I) which are substituted at the 4-position of the pyrimidine ring can be prepared as outlined in Scheme 10. 
Known pyrimidine (XXXV), synthesis of which is reported in Eur. J. Med. Chem. 23:60 (1988), can be reacted with a substituted aniline (IV) in an analogous manner to Scheme 1. Treatment of the hydroxy group in (XXXVI) with either phosphorous oxychloride, phosphorous oxybromide, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride provided (XXXVII), wherein the L is a leaving group. Alkylation under the standard conditions gives (XXXVIII). The L group of (XXXVIII) was displaced with a nucleophile such as NR6R7, OR6, SR6, CN, or an organometallic reagent to the corresponding adduct (XXXIX).
Compounds of the Formula (I), wherein X or Xxe2x80x2 is alkylmercapto, or functionalized alkylmercapto can be synthesized under the conditions described in Scheme 11. 
Treatment of the appropriately ortho-functionalized aniline XXXIX with a substituted 2-mercaptopyrimidine XL in the presence of a base such as potassium carbonate, sodium carbonate, alkali metal alkoxide, potassium sodium or lithium hydride, a lithium, sodium or potassium dialkylamide, or an alkali metal in the presence of copper powder or copper salts gives the corresponding aryl sulfide XLI which is subjected to a Smiles rearrangement by treatment with an strong acid such as hydrochloric, hydrobromic, hydriodic, sulfuric, phosphoric or perchloric, to give the corresponding disulfide XLIII. This is reduced to the sulfide XLIV with a reducing agent such as sodium borohydride and alkylated on the sulfur with the appropriate alkylating agent such as an alkyl halide, tosylate or mesylate. The rearrangement of XLI may be carried out with a strong base such as lithium, sodium, or potassium hydride; lithium, sodium, or potassium dialkylamide; or lithium sodium or potassium metal, in an appropriate solvent such as decahydronaphthalene, xylenes, high boiling alcohols, dimethylformamide, dimethylsulfoxide, dimethylacetamide, and N-methylpyrrolidinone. The rearrangement product can be selectively alkylated on the sulfur with the use of a base such as potassium, sodium or lithium carbonate, potassium, sodium or lithium alkoxide, or trialkylamine and the appropriate alkylating agent as described above. The alkylsulfide can be further alkylated on the nitrogen by using identical conditions as described above to yield compound XLV.
Compounds of formula (I), wherein R3 is (CH2)kOR8 and R8 is (CH2)tC(xe2x95x90O)OR24, (CH2),C(xe2x95x90O)NR6R7, or (CH2)tNR6R7 can be made according to Scheme 12. 
Compounds XLVII, XLVIII, and XLIX are made using the product of Example 24 as starting material by procedures analogous to those used to make the products of Examples 25, 16, and 17 respectively.
The novel 7-azaindoles of the present invention are prepared by Scheme 13 outlined below. The potassium salt of formylsuccinonitrile is treated with the appropriate substituted aniline L to give LI. This undergoes base catalyzed cyclization to a 1-aryl-2-amino-4-cyanopyrrole LII. Reaction with an appropriate 1,3-dicarbonyl compound gives the desired 7-azaindole LIII. 
The nitrile substituent at position 3 of structure LIII is readily removed by refluxing the 3-cyano compound with 65% sulfuric acid. Position 3 then can be resubstituted by halogenation or nitration. Reduction of the nitro group can provide the 3-amino substituent.
Alternatively, the nitrile group can be converted to desired L groups by methods described in xe2x80x9cComprehensive Organic Transformationsxe2x80x9d, by Richard C. Larock, VCH Publishers, Inc., New York, N.Y., 1989. For instance, the nitrile group can be reduced with diisobutylaluminum hydride to give the 3-aldehyde. The 3-aldehyde can be reduced via the hydrazone under Wolff-Kishner conditions (KOH in hot diethylene glycol) to give L=methyl. Furthermore, the aldehyde can be converted to Lxe2x95x90CHxe2x95x90CH2 by adding it to a mixture of methyltriphenylphosphonium bromide and potassium tertiary-butoxide in tetrahydrofuran (Wittig reaction). Reduction of the ethenyl group to give Lxe2x95x90CH2CH3 can be effected by hydroboration-protonolysis (J. Am. Chem. Soc. 81:4108(1959)).
Scheme 13 generally provides a mixture isomeric in substituents R1 and R3, which then can be separated, Sometimes the preferred isomer is the one obtained in lower yield. In that event Scheme 14 can be used to prepare the preferred isomer. Intermediate LII is treated with the appropriate acyl- or aroyl-acetic ester under either thermal or acid-catalyzed conditions to give the 6-hydroxy compound LV. Compound LV is converted to the 6-chloro compound LVI and de-cyanylated to compound LVII. When R1 substituents other than chloro are desired, the chloro group can be converted to other substituents. For instance, treatment of compound LVII with an alkyl Grignard reagent can provide compound LVIII where R1=alkyl. Heating with a primary or secondary amine can provide compound LVIII where R1=amino. 
Scheme 15 affords another route to compounds of this invention. Intermediate LII can be treated with the appropriate acylacetaldehyde dialkyl acetal under acid catalyzed conditions to give compounds LXa and LXb, 7-azaindoles unsubstituted at positions 4 and 6 respectively. Compound LXa can be oxidized with m-chloroperoxybenzoic acid to give the N-oxide compound LXI. Heating compound LXI with phosphorus oxychloride can give compound XIIa, which can be decyanylated to compound LXIII.
Compound LXIV where R3 is an amino substituent can be prepared by heating LXIII with the appropriate amine; where R3=alkoxide, the metal alkoxide can be heated with LXIII; where R3=aryl, compound LXIII can treated with the arylboronic acid in the presence of tetrakis(triphenylphosphine)p alladium (TTPP) and sodium carbonate; and where R3=alkyl, alkenyl, aralkyl, and cycloalkyl, compound LXIII can be coupled with the appropriate organotin reagent, also in the presence of 7TPP.
Compound LXIV where R3 is a nitro group can be prepared by nitration of LXI, decyanylation, and reduction of the N-oxide with a trivalent phosphorus compound such as triethyl phosphite.
Compound LXb can be substituted in the 6 position using methods described for the substitution of LXa. 
The novel 7-azabenzimidazoles of this invention can be prepared as outlined in Scheme 16 where R29 is nitrogen. Compounds L and LXV can react upon heating in the presence of a base, e.g. sodium hydride, to give the diarylamine LXVI. Reduction of the nitro group with stannous chloride can give LXVII, which can be closed to the 7-azabenzimidazole LXVIII. 
The purines of this invention can be prepared as shown in Schemes 17 and 18.
Compounds L and LXIX (J. Heterocyclic Chem. 28:465 (1991)) can be heated in the presence of a base, e.g. sodium hydride, to give compound LXX. Heating LXX with the appropriate carboxylic acid in the presence of a mineral acid catalyst can give LXXI where R28 is hydrogen, alkyl, alkenyl, or alkynyl. The chloro substituent can then be converted to R3 to give compounds LXXII by using one of the methods described above for the introduction of R3 to obtain compounds LXIV. 
Scheme 18 can be used to prepare purines where R28 is halogen or alkoxide. Compounds LXX can be heated with a dialkyl carbonate, such as diethyl carbonate, to give the carbonyl compound LXXIII; if the conversion is undesirably slow, more reactive species such as trichloromethyl chlorocarbonate or carbonyl diumidazole can be used in place of diethyl carbonate. The chloro substituent can then be converted to R3 to give LXXIV by using one of the methods described above for the introduction of R3 to obtain LXIV. Heating LXXIV with phosphorus oxychloride can give the 2-chloropurine, LXXV. To prepare the 2-alkoxypurines, LXXVI, LXXV can be heated with a metal salt of the alcohol R31OH, e.g. the sodium or potassium salt, wherein in R31 is C1-C4 alkyl. 
The method of synthesis of the 7-azaindolines of this invention is shown in Scheme 19.
A number of compounds of the general structure LXXVIII with desired R1 and R2 groups have been described by W. Paudler and T.-K. Chen, J. Heterocyclic Chem. 7:767 (1970). These can be oxidized with a peracid, e.g. m-chloroperoxybenzoic acid, to the sulfone LXXIX. Sulfone LXXIX can be heated in the presence of the desired aniline and a base, e.g. sodium hydride to give the diaryl amine LXXX. Alkylation of LXXX with the desired unsubstituted or 4-substituted 3-butynyl iodide (or 3-butynol mesylate) can give LXXXI. LXXXI can undergo an intramolecular Diels-Alder reaction to give LXXXII.
In a number of cases, the desired 4-substituted 3-butynyl iodide is not readily available or is unstable. In that event unsubstituted 3-butynyl iodide is used to give compound LXXXII where R3=H. 
The synthesis of the 5,7-diazaindoles of this invention is outlined in Scheme 20.
The desired formamidine LXXXIII can be treated with LXXXIV in the presence of sodium ethoxide in ethanol to give the pyrimidine LXXXV. Refluxing LXXXV in phosphorus oxychloride gives the dichloropyrimidine LXXXVI. Compound LXXXVI can be converted to the carbonyl compound LXXXVII by treatment with one equivalent of ozone at xe2x88x9278xc2x0 to give an ozonide, which on treatment with sodium iodide and acetic acid gives the desired carbonyl compound. The preparation of LXXXVII (R1=H, R28=CH3 and R1=R28=CH3) by a different route has been described by E. Basagni et al., Bull. Soc. Chim. Fr., 4338 (1969).
Before the coupling reaction, the carbonyl of compound LXXXVII is protected by treatment with 2,2-dimethoxypropane in the presence of a catalytic amount of acid to give compound LXXXVIII. Compound LXXXVIII is then coupled with the appropriate aniline L by heating in the presence of a base, e.g. sodium hydride, to give compound LXXXIX. Compound LXXXIX can be cyclized to give the 5,7-diazaindole XC, the target compound wherein R3=Cl. Compound XC is also a useful intermediate for the preparation of Compounds XCI with other R3 groups. For example, heating the chloro compound with the appropriate amine gives the desired amino compound. Heating with a metal alkoxide gives the desired alkoxy compound. Treating compound XC (R3=Cl) with R3MgBr (R3=alkyl, aryl, or aralkyl) converts the chloro compound to the desired alkyl, aryl, or aralkyl compound XCI. 
Compounds wherein R5 is dimethylhydroxymethyl, Xxe2x80x2 is iodine and R1 and R3 are chlorine can be prepared according to scheme 21. Ethyl 4-aminobenzoate is iodinated in a methylene chloride/water (50:50) mixture in the presence of sodium bicarbonate to provide compound (XCII). This material is coupled to cyanuric chloride, then the secondary amine is alkylated in an analogous manner to that in Scheme 1 to yield XCIII. Compound XCIII is treated with 5 equivalents of MeMgBr to provide the desired material of formula (XCIV). 
Scheme 22 depicts the synthesis of compounds of Formula (I), where Y=N, Z=CR2 and R3 is COR25, CH(OH)R25 or C(OH)R25R25a. An ester of Formula (XCVI) may be converted to an amide of Formula (C) by treatment with an amine of Formula HN(ORa)Rb, where Ra and Rb are lower alkyl (preferably Me), in the presence of a trialkylaluminum reagent (preferably Me3Al) in an inert solvent preferably an aromatic hydrocarbon (e.g., benzene) or an ethereal solvent (e.g., tetrahydrofuran) as taught by the prior art (cf. J. I. Levin, E. Turos, S. M. Weinreb, Synthetic Communications 12:989-993 (1982)). Amides of Formula (C) may be converted to ketones of Formula (CI) by treatment with an organolithium reagent R25Li or an organomagnesium halide R25MgX, where X=Cl, Br or I, in an inert solvent, preferably an ethereal solvent (e.g., diethyl ether or tetrahydrofuran), as taught by the prior art (cf. S. Nahm and S. M. Weinreb, Tetrahedron Letters 22:3815-3818 (1981)). Alternatively, ketones of Formula (CI) can be prepared from acids of Formula (XCV) by treatment with an organolithium reagent R25Li in the presence of an inorganic salt (preferably a transition metal halide (e.g., CeCl3)) in an inert solvent (preferably an ethereal solvent (e.g., tetrahydrofuran)) as taught by the prior art (cf. Y. Ahn and T. Cohen, Tetrahedron Letters 35:203-206 (1994)). Alternatively, esters of Formula (XCVI) can be converted directly to ketones of Formula (XCVIII) by reaction with an organolithium reagent R25Li or an organomagnesium halide R25MgX, where X=Cl, Br or I, in an inert solvent (preferably an ethereal solvent e.g., diethyl ether or tetrahydrofuran) at temperatures ranging from xe2x88x92100 to 150xc2x0 C. (preferably xe2x88x9278 to 80xc2x0 C.) (cf. J. March, Advanced Organic Chemistry (New York: J. Wiley and Sons, 1985, pp.433-434). Ketones of Formula (XCVIII) can be converted to alcohols of Formula (XCIX) by reaction with an organolithium reagent R25Li or an organomagnesium halide R25MgX, where X=Cl, Br or I, in an inert solvent (preferably an ethereal solvent (e.g. diethyl ether or tetrahydrofuran) at temperatures ranging from xe2x88x92100 to 150xc2x0 C. (preferably xe2x88x9278 to 80xc2x0 C.) (cf. the above March reference, pp. 434-435). Alternatively, esters of Formula (XCVI) can be converted to alcohols of Formula (XCIX) by reaction with an organolithium reagent R25aLi or an organomagnesium halide R25aMgX, where X=Cl, Br or I, in an inert solvent (preferably an ethereal solvent e.g., diethyl ether or tetrahydrofuran) at temperatures ranging from xe2x88x92100 to 150xc2x0 C. (preferably xe2x88x9278 to 100xc2x0 C.), preferably using an excess amount of organometallic reagent (cf. the above March reference, pp. 434-435). In this last instance, R25=R25. Ketones of Formula (XCVIII) can be converted to alcohols of Formula (C) by treatment with a reducing agent in an inert solvent. Such reducing agents include, but are not limited to, alkali metal aluminum hydrides, preferably lithium aluminum hydride, alkali metal borohydrides (preferably sodium borohydride), alkali metal trialkoxyaluminum hydrides (such as lithium tri-t-butoxyaluminum hydride), dialkylaluminum hydrides (such as di-isobutylaluminum hydride), borane, dialkylboranes (such as di-isoamyl borane), alkali metal trialkylboron hydrides (such as lithium triethylboron hydride). Inert solvents include lower alkyl alcohols of 1 to 6 carbons, ethereal solvents (such as diethyl ether or tetrahydrofuran), aromatic or non-aromatic hydrocarbons of 6 to 10 carbons. Reaction temperatures for the reduction range from about xe2x88x9278xc2x0 to about 200xc2x0 C., preferably about 0xc2x0 to about 120xc2x0 C. The choice of reducing agent and solvent is known to those skilled in the art as taught in the above cited March reference (Advanced Organic Chemistry, pp. 1093-1110). 
Compounds of Formula (I) can also be prepared by the procedures outlined in Scheme 23. A compound of Formula (CI) (Formula I, where Z=CR2, Y=N, R3=(CHR11)pCN) can be reacted with sodium azide and ammonium chloride in a polar solvent at high temperatures (preferably 70 to 150xc2x0 C.) to give a tetrazole of Formula (CII) as taught by the prior art (cf. R. N. Butler, Tetrazoles, in Comprehensive Heterocyclic Chemistry; A. R. Katritzky, C. W. Rees, Eds.; (New York: Pergamon Press, 1984), pp. 828-832). Such polar solvents may be dialkylformamides (preferably N,N-dimethylformamide), dialkylacetamides, (preferably N,N-dimethylacetamide), cyclic amides, (preferably N-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethyl sulfoxide) or dioxane. A compound of Formula (CIII) (Formula I, where Y=N, Z=CR2 and R3=COCH3) may be treated with a halogenating agent in an inert solvent to give a haloketone of Formula (CIV). Such halogenating agents include bromine, chlorine, iodine, N-halosuccinimides (e.g. N-bromosuccinimide), N-halophthalimides (e.g., N-bromophthalimide) or N-tetrasubstituted ammonium perbromides (e.g., tetraethylammonium perbromide) (cf. the above March reference, Advanced Organic Chemistry, pp. 539-531; S. Kajigaeshi, T. Kakinami, T. Okamoto, S. Fujisaki, Bull. Chem. Soc. Japan 60:1159-1160 (1987) and references cited therein). Inert solvents include lower halocarbons of 1 to 6 carbons and 2 to 6 halogens (preferably dichloromethane or dichloroethane), dialkyl ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons (preferably dioxane) or aromatic hydrocarbons to 6 to 10 carbons. Haloketones of Formula (CIV) may be converted to imidazoles of Formula (CVII) by treatment with formamide with or without an inert solvent as taught by the prior art (H. Brederick and G. Theilig, Chem. Ber. 86:88-108 (1953)). Alternatively, ketones of Formula (CIII) may be converted to vinylogous amides (CV) by reaction with N,N-di(lower alkyl)formamide di(lower alkyl)acetals (e.g., N,N-dimethylformamide dimethyl acetal) or Gold""s reagent ((dimethylaminomethyleneaminomethylene)-dimethylammonium chloride) in an inert solvent with or without base as taught by the prior art (cf. J. T. Gupton, S. S. Andrew, C. Colon, Synthetic Communications 12:35-41 (1982); R. F. Abdulla, K. H. Fuhr, J. Organic Chem. 43:4248-4250 (1978)). Such inert solvents include aromatic hydrocarbons of 6 to 10 carbons, lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, or cyclic ethers of 4 to 10 carbons (preferably dioxane). Such bases may include a tertiary amine, an alkali metal hydride (preferably sodium hydride), an aromatic amine (preferably pyridine), or an alkali metal carbonate or alkoxide. Vinylogous amides (CV) can be condensed with hydrazine in an inert solvent to form pyrazoles of Formula (CVI) as taught by the prior art (cf. G. Sarodnick, Chemische Zeitung 115:217-218 (1991); Y. Lin, S. A. Lang, J. Heterocyclic Chem. 14:345 (1977); E. Stark et al., Chemische Zeitung 101:161 (1977); J. V. Greenhill, Chem. Soc. Reviews 6:277 (1977)). Such inert solvents include aromatic hydrocarbons of 6 to 10 carbons, lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, or cyclic ethers of 4 to 10 carbons (preferably dioxane). 
The purines and 8-aza-purines of the present invention are readily synthesized following the methods shown in Schemes 24 and 25. The purine (CXI) is derived from an appropriately substituted pyrimidine (CVIII). The trisubstituted hydroxypyrimidine is nitrated under standard conditions with fuming nitric acid. Following conversion of the hydroxy compound to the chloro derivative via treatment with phosphorus oxychloride, reduction of the nitro group with iron powder in acetic acid and methanol yielded the aminopyrimidine (CIIX). Compound CIIX is reacted with the appropriately substituted aniline in the presence of base catalyst to yield an anilinopyrimidine (CX), which was then converted to the desired purine (CXI) via reaction with triethylorthoformate in acetic anhydride. Starting from compound CX, the desired 8-aza-purine can be prepared via reaction with sodium nitrite in acetic acid. 
If R3 of the purine is a chloro group, that substituent can be further elaborated to other R3 substituents as shown in Scheme 25. Compound (CXII), wherein R3 is chlorine, is reacted with a nucleophile with or without an inert solvent at temperatures ranging from 20xc2x0 C. to 200xc2x0 C., to effect the formation of the 8-azapurine (CXIII). In a similar fashion, the R3 of an appropriately substituted purine (CXI) may be converted to other functional groups to yield the purine (CXIV) having the desired substitution pattern. Similarly, if R1 is a chloro group, it may be converted to another functional group via reaction with an appropriate nucleophile. Nucleophiles include amine, hydroxy, or mercapto compounds or their salts. 
Compounds of the Formula (I) wherein J, K, and/or L are N, such as (CXXVII), (CXXVIII), (CXXIX), or (CXXX), were prepared according to Schemes 26 and 27. The preparation of the lower ring heterocycle of the compound of the Formula (I) is shown in Scheme 26. 2,4-Dihydroxy-5-nitropyrimidine (CXV) was first converted to the dichloro compound (CXVI) via treatment with phosphorus oxychloride. Compound (CXVI) was then converted to the symmetrically bis-substituted pyrimidines, (CXVII) and (CXVIII), via reaction with the appropriate R5 or X group radicals, MR5 and MX, respectively, where M is a metal atom. It is understood that compounds of the Formula (I) wherein R5 and X have the same definition fall within the scope of this invention. A method of forming the unsymmetrically bis-substituted compounds (CXIX) and (CXX) is treatment of (CXVI) with equimolar amounts of MR5 and X to form a statistical distribution of products, (CXVII), (CXVIII), (CXIX) and (CXX), which can be purified by standard techniques, such as, recrystallization or chromatography,
The desired (N-pyrimidino-N-alkyl)aminopyrimidines of the present invention were prepared according to Scheme 27. An appropriately substituted 2-hydroxypyrimidine (CXXI) was converted to the 2-chloropyrimidine (CXXII) via treatment with phosphorus oxychloride. The intermediate (N-pyrimidino)aminopyrimidines, (CXXIII), (CXXIV), (CXXV), and (CXXVI), were prepared via treatment of (CXXII) with the appropriate 5-aminopyrimidine, (CXVII), (CXVIII), (CXIX) and (CXX) respectively, in the presence of a base, such as, NaH. Simple alkylation of the amino groups in (CXXIII), (CXXIV), (CXXV), and (CXXVI) via treatment with R4I and sodium hydride gave the desired (N-pyrimidino-N-alkyl)aminopyrimidines, (CXXVII), (CXXVIII), (CXXIX), and (CXXX). 
The (N-heterocycle-N-alkyl)aminopyrimidines or N-heterocycle-N- alkyl)aminotriazines of the present invention may also be prepared according to Scheme 28. Commercially available amino substituted heterocycles (CXXXI) may be brominated using a tetrasubstituted ammonium tribromide, preferably benzyltrimethylammonium tribromide (BTMA Br3) to yield the appropriately substituted o-bromo-aminoheterocycle (CXXXII). Such reactions are carried out in an inert solvent, such as, lower alcohols or halocarbons of 1 to 4 carbons and 1 to 4 halogens in the presence of a base, such as, alkali metal or alkaline earth metal carbonates. Compound (CXXXII) is then coupled to a substituted pyrimidine or triazine (CXXXIII) to form an (N-heterocycle)aminopyrimidine (CXXXIVa) or (N-heterocycle)aminotriazine (CXXXIVb). (CXXXIVa or b) is then further alkylated in the presence of a base to the target (N-heterocycle-N-alkyl)aminopyrimidine (CXXXVa) or (N-heterocycle-N-alkyl)aminotriazine (CXXXVb), respectively. 